Stabilized oral pharmaceutical composition

ABSTRACT

An orally deliverable pharmaceutical composition is provided comprising an aminosulfonyl-comprising drug, for example a selective cyclooxygenase-2 inhibitory drug such as celecoxib, and a solvent liquid comprising a polyethylene glycol and one or more free radical-scavenging antioxidants. At least a substantial part of the drug is in dissolved form in the solvent liquid. The composition has rapid-onset properties and is useful in treatment of cyclooxygenase-2 mediated conditions and disorders.

[0001] This application claims priority of U.S. provisional patentapplication Serial No. 60/284,589 filed on Apr. 17, 2001, and of U.S.provisional patent application Serial No. 60/357,959 filed on Feb. 19,2002.

FIELD OF THE INVENTION

[0002] The present invention relates to orally deliverablepharmaceutical compositions that comprise a drug of low watersolubility, more particularly to such compositions where the drug is indissolved form.

BACKGROUND OF THE INVENTION

[0003] Several compounds having a molecular structure that comprises anaminosulfonyl functional group (herein referred to asaminosulfonyl-comprising compounds) have been reported as havingtherapeutically and/or prophylactically useful selectivecyclooxygenase-2 (COX-2) inhibitory effects, and have been disclosed ashaving utility in treatment or prevention of specific COX-2 mediateddisorders or of such disorders in general. Among such compounds are alarge number of substituted pyrazolyl benzenesulfonamides as reported inU.S. Pat. No. 5,760,068 to Talley et al., including for example thecompound4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,also referred to herein as celecoxib (I), and the compound4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,also referred to herein as deracoxib (II).

[0004] Other aminosulfonyl-comprising compounds reported to havetherapeutically and/or prophylactically useful selective COX-2inhibitory effect are substituted isoxazolyl benzenesulfonamides asreported in U.S. Pat. No. 5,633,272 to Talley et al., including thecompound 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, alsoreferred to herein as valdecoxib (III).

[0005] A need for formulated compositions of selective COX-2 inhibitorydrugs, particularly rapid-onset compositions of such drugs, exists.Rapid-onset drug delivery systems can provide many benefits overconventional dosage forms. Generally, rapid-onset preparations provide amore immediate therapeutic effect than standard dosage forms. Forexample, in the treatment of acute pain, for example in headache ormigraine, rapid-onset dosage forms are useful to provide fast painrelief.

[0006] Australian Patent Applications No. 200042711, No. 200043730 andNo. 200043736 disclose compositions comprising a selective COX-2inhibitory drug, a 5HT₁ receptor agonist and caffeine, said to be usefulfor treating migraine.

[0007] U.S. Pat. No. 5,993,858 to Crison & Amidon discloses an excipientformulation for increasing bioavailability of a poorly water-solubledrug. The formulation is said to be self-microemulsifying and tocomprise an oil or other lipid material, a surfactant and a hydrophilicco-surfactant. The choice of surfactant is said to be less critical thanthe choice of co-surfactant, which reportedly should have an HLB(hydrophilic-lipophilic balance) number greater than 8. A preferredexample of such a co-surfactant is said to be Labrasol™ of Gattefosse,identified as a product “comprised of medium-chain triglycerides derivedfrom coconut oil” having HLB of 14. A formulation prepared containing 15mg nifedipine in a size 1 (0.5 ml) capsule, i.e., at a concentration of30 mg/ml, is described as a “clear solution” at 70° C. but a“semi-solid” at room temperature.

[0008] Cited in above-referenced U.S. Pat. No. 5,993,858 is prior workby Farah et al. in which a self-microemulsifying formulation wasinvestigated for improving in vitro dissolution of indomethacin. Theformulation of Farah et al. reportedly comprised an oil phase materialGelucire™ of Gattefossé, together with a polyethylene glycolcapric/caprylic glyceride product having HLB of 10, a propylene glycollaurate product having HLB of 4, and diethylene glycol monoethyl ether.

[0009] Drugs of low water solubility are sometimes orally administeredin suspension in an imbibable aqueous liquid. For example, a suspensionof particulate celecoxib in a vehicle of apple juice is disclosed inco-assigned International Patent Publication No. WO 00/32189,incorporated herein by reference. Also disclosed therein is a dilutesolution of celecoxib in a mixture of PEG-400 (polyethylene glycolhaving an average molecular weight of about 400) and water in a 2:1ratio by volume.

[0010] The suspension and solution compositions of WO 00/32189 areindicated therein to have comparable bioavailability. However, followingoral administration to dogs, the time taken for blood serum celecoxibconcentration to reach a maximum level (T_(max)) was shorter for thesolution composition than for the suspension.

[0011] Above-cited U.S. Pat. No. 5,760,068 discloses that its subjectpyrazolyl benzenesulfonamide compounds, of which celecoxib and deracoxibare examples, can be administered parenterally as isotonic solutions ina range of solvents including polyethylene glycol and propylene glycol.It is also disclosed therein that the subject compounds canalternatively be present in a controlled-release capsule or tabletformulation for oral administration wherein, for example, such acompound is dispersed in hydroxypropylmethylcellulose (HPMC).

[0012] Above-cited U.S. Pat. No. 5,633,272 discloses that its subjectisoxazolyl benzenesulfonamides, of which valdecoxib is an example, canbe administered parenterally as isotonic solutions in a range ofsolvents including polyethylene glycol and propylene glycol. It is alsodisclosed therein that the subject compounds can alternatively bepresent in a controlled-release capsule or tablet formulation for oraladministration wherein, for example, such a compound is dispersed inHPMC.

[0013] It is known to encapsulate liquid formulations, for example insoft or hard gelatin capsules, to provide a discrete dosage form.

[0014] Many aminosulfonyl-comprising selective COX-2 inhibitory drugs,including celecoxib, deracoxib and valdecoxib, have low solubility inaqueous media. In addition, some, for example celecoxib, have relativelyhigh dose requirements. These properties present practical problems informulating concentrated solutions of such drugs for rapid-onset, oraladministration. With respect to high dose, low solubility drugs, thesize of the capsule or volume of solution required to provide atherapeutic dose becomes a limiting factor. For example, a drug that hasa solubility of 10 mg/ml in a given solvent and a therapeutic dose of400 mg/day would require ingestion of 40 ml of solution. Such a volumecan be inconvenient or unacceptable for consumption in imbibable form;this volume also presents particular problems where an encapsulateddosage form is desired because capsules that contain more than about 1.0ml to about 1.5 ml of liquid are generally considered to be too largefor comfortable swallowing. Thus, where such a solution is administeredin capsule form, multiple capsules would need to be ingested in order toprovide the required dose. To avoid such problems, a solvent must beselected wherein the drug has relatively high solubility.

[0015] Moreover, the solvent should be selected not to chemicallyinteract with or degrade the drug. For solutions and/or suspensions thatare to be encapsulated as oral dosage forms, the solvent must further beselected not to degrade, erode, or react with the capsule wall material.Further, liquids that can easily migrate through a capsule wall, e.g.,water in an amount greater than about 5% by weight of the solution, andlow molecular weight water-soluble, volatile organic compounds such asalcohols, ketones, acids, amines and esters, are generally unsuitablefor encapsulation.

[0016] Water-miscible, nonvolatile liquids such as polyethylene glycolshave been successfully used in encapsulated solution formulations.Moreover, polyethylene glycols are also good solvents for drugs of lowwater solubility because they are known to improve aqueous drugsolubility. For example, celecoxib, which has very low solubility inwater, is highly soluble (>300 mg/g) in a 2:1 mixture of PEG-400 andwater.

[0017] However, we have now discovered that polyethylene glycol, whenused as a solvent for an aminosulfonyl-comprising drug such ascelecoxib, can result in drug instability. This problem presentspractical difficulties in forming a chemically stable solution of anaminosulfonyl-comprising drug using polyethylene glycol (which, asdescribed above, can be otherwise advantageous) as a solvent.

[0018] As described hereinbelow, treatment with selective COX-2inhibitory drugs of low water solubility is indicated in a very widearray of COX-2 mediated conditions and disorders, and several clinicallyimportant examples of such drugs comprise an aminosulfonyl functionalgroup. Therefore, if the problem of chemical instability of the drug inpolyethylene glycol solution could be overcome, a significant advancewould be realized in treatment of COX-2 mediated conditions anddisorders, particularly in treatment of acute disorders where earlyrelief from pain or other symptoms is desired. It would represent anespecially important advance in the art to provide an effective methodof treatment of acute pain, for example in headache or migraine, using achemically stable solution of an aminosulfonyl-comprising selectiveCOX-2 inhibitory drug having polyethylene glycol as a solvent, if such asolution could be prepared.

SUMMARY OF THE INVENTION

[0019] There is now provided an orally deliverable pharmaceuticalcomposition comprising a drug of low water solubility and a solventliquid that comprises at least one pharmaceutically acceptablepolyethylene glycol and at least one pharmaceutically acceptable freeradical-scavenging antioxidant, wherein a substantial portion, forexample at least about 15% by weight, of the drug is in dissolved orsolubilized form in the solvent liquid, and wherein the drug comprisesan aminosulfonyl functional group and/or is capable of reacting with apolyethylene glycol or polyethylene glycol degradation product to forman addition compound.

[0020] The term “solvent liquid” herein encompasses all of thecomponents of the liquid medium in which a particular drug is dissolvedor solubilized including but not limited to one or more solvents,co-solvents, antioxidants, crystallization inhibitors, dispersants,surfactants, co-surfactants, sweeteners, flavoring agents, colorants,etc.

[0021] In a presently preferred composition of the invention,substantially all of the drug is in dissolved or solubilized form in thesolvent liquid and substantially none of the drug is in solidparticulate form. Such a composition is referred to herein as a“solution”. It is particularly preferred that the solution is finelyself-emulsifiable in simulated gastric fluid, as described hereinbelow.

[0022] An alternative composition of the invention comprises, inaddition to a first portion of the drug in dissolved or solubilizedform, a second portion of the drug in particulate form dispersed in thesolvent liquid. In this embodiment, part of the drug is in solution andpart is in suspension. Such a composition is referred to herein as a“solution/suspension”.

[0023] In a presently preferred embodiment, the solution orsolution/suspension is encapsulated in one or more capsules that releasethe drug by capsule wall breakdown within a short period of time afterentry into the gastrointestinal tract. In this embodiment, the capsulewall optionally comprises a cellulosic polymer component whereinhydroxyl groups are substituted by methoxyl and/or hydroxypropoxylgroups, for example HPMC.

[0024] Compositions of the invention have been found to resolve theproblem of drug instability in a surprisingly effective manner. Thus,for the first time, a poorly water-soluble drug that comprises anaminosulfonyl functional group, and/or is capable of reacting with apolyethylene glycol or polyethylene glycol degradation product to forman addition compound, is presented in a stable, concentrated solutionformulation having a polyethylene glycol as a solvent. Preferably suchformulations are presented in a dose form that is convenient for oraladministration. Formulations of the invention are particularlyadvantageous because they are chemically stable, permit a highconcentration of the drug, are suitable for encapsulation, and,following oral administration thereof, can permit rapid absorption ofthe drug into the bloodstream thereby providing rapid onset oftherapeutic action.

[0025] It can be theorized that a poorly water-soluble drug can providemore rapid onset of therapeutic effect when orally administered insolution, particularly a self-emulsifiable solution, than in particulateform because the process of dissolution in the gastrointestinal tract isnot required. An even greater advantage by comparison with a solidformulation such as a tablet can be postulated because neitherdisintegration nor dissolution is required in the case of the solutioncomposition.

[0026] Additionally, a drug administered in imbibable solution can beavailable for absorption higher in the alimentary tract, for example, inthe mouth and esophagus, than one that becomes available for absorptiononly upon disintegration of the carrier formulation in the stomach orbowel.

[0027] A further advantage of liquid dosage forms such as imbibablesolutions and solution/suspensions for many subjects is that thesedosage forms are easy to swallow. A yet further advantage of imbibableliquid dosage forms is that metering of doses is continuously variable,providing infinite dose flexibility. The benefits of ease of swallowingand dose flexibility are particularly advantageous for infants, childrenand the elderly.

[0028] When encapsulated, a solution or solution/suspension can providethe subject with the beneficial rapid absorption characteristicsassociated with liquid formulations in addition to the convenience of adiscrete, easy to swallow capsule form.

[0029] The highly concentrated solutions permitted by the presentinvention are beneficial for several reasons. First, concentratedsolutions are less costly to package and easier to transport and handlethan dilute solutions. Second, concentrated solutions provideflexibility in administration as they can be administered with anydesired degree of dilution. And third, concentrated drug solutions,especially when encapsulated, do not require consumption of largevolumes of fluid, which can be uncomfortable for many patientpopulations.

[0030] In one embodiment, a method of analgesia is provided comprisingorally administering, to a subject in need of analgesia, an effectivepain-relieving amount of an aminosulfonyl-comprising selective COX-2inhibitory drug composition of the invention. In another embodiment, amethod of treatment and/or prevention of headache or migraine isprovided comprising orally administering, to a subject in need of suchtreatment or prevention, an aminosulfonyl-comprising selective COX-2inhibitory drug composition of the invention and a vasomodulator, forexample a methylxanthine, wherein the selective COX-2 inhibitory drugand the vasomodulator are administered in effective pain-relieving totaland relative amounts. The selective COX-2 inhibitory drug and thevasomodulator can be administered as components of separate compositionsor of a single composition. Such a single composition comprising (a) anaminosulfonyl-comprising selective COX-2 inhibitory drug, formulated asprovided herein, and (b) a vasomodulator, is a further embodiment of theinvention. A presently preferred methylxanthine is caffeine.

[0031] Other features of this invention will be in part apparent and inpart pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Novel pharmaceutical compositions according to the presentinvention comprise one or more orally deliverable dose units. The term“orally deliverable” herein means suitable for oral administration. Theterm “oral administration” herein includes any form of delivery of atherapeutic agent or a composition thereof to a subject wherein theagent or composition is placed in the mouth of the subject, whether ornot the agent or composition is swallowed. Thus “oral administration”includes buccal and sublingual as well as esophageal administration.Absorption of the agent can occur in any part or parts of thegastrointestinal tract including the mouth, esophagus, stomach,duodenum, jejunum, ileum and colon. The term “dose unit” herein means aportion of a pharmaceutical composition that contains an amount of atherapeutic agent suitable for a single oral administration to provide atherapeutic effect. Typically one dose unit, or a small plurality (up toabout 4) of dose units, provides a sufficient amount of the agent toresult in the desired effect.

[0033] Aminosulfonyl-Comprising Drug

[0034] Each dose unit or small plurality of dose units comprises, in atherapeutically and/or prophylactically effective total amount, a drugof low water solubility that comprises an aminosulfonyl functional groupand/or is capable of reacting with a polyethylene glycol or apolyethylene glycol degradation product to form an addition compound. A“drug of low water solubility” or “poorly water solubility drug” hereinrefers to any drug compound having a solubility in water, measured at37° C., not greater than about 10 mg/ml, and preferably not greater thanabout 1 mg/ml. It is contemplated that compositions of the invention areespecially advantageous for drugs having a solubility in water, measuredat 37° C., not greater than about 0.1 mg/ml.

[0035] It will be understood that a therapeutically and/orprophylactically effective amount of a drug for a subject is dependentinter alia on the body weight of the subject. A “subject” herein towhich a therapeutic agent or composition thereof can be administeredincludes a human patient of either sex and of any age, and also includesany nonhuman animal, particularly a domestic or companion animal,illustratively a cat, dog or horse.

[0036] The term “aminosulfonyl functional group” herein refers to afunctional group having the following structure:

[0037] wherein the wavy line represents a bond by which the functionalgroup is attached to the rest of the drug molecule; and R is hydrogen ora substituent that preserves ability of polyethylene glycol or apolyethylene glycol degradation product to react with the amino groupadjacent to R to form an addition compound. Illustrative examples ofsuch substituents include partially unsaturated heterocyclyl,heteroaryl, cycloalkenyl, aryl, alkylcarbonyl, formyl, halo, alkyl,haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl,alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl,alkoxyalkyloxyalkyl, haloalkylsulfonyloxy, carboxyalkoxyalkyl,cycloalkylalkyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl,heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl,heteroarylcarbonyl, alkylthioalkyl, areylcarbonyl, aralkylcarbonyl,aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino,N-alkyl-N-aralkylamino, N-alkyl-Narylamino, Aminoalkyl, alkylaminoalkyl,N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,alkylsufinyl, alkylsulfonyl, etc.

[0038] Non-limiting illustrative examples of aminosulfonyl-comprisingdrugs include ABT-751 of Eisai(N-(2-((4-hydroxyphenyl)amino)-3-pyridyl)4-methoxybenzene-sulfonamide);alpiropride; amosulalol; amprenavir; amsacrine; argatroban; asulacrine;azosemide; BAY-38-4766 of Bayer(N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-3-hydroxy-2,2-dimethylpropanamide);bendroflumethiazide; BMS-193884 of Bristol Myers Squibb(N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)-[1,1′-biphenyl]-2-sulfonamide);bosentan; bumetamide; celecoxib; chlorthalidone; delavirdine; deracoxib;dofetilide; domitroban; dorzolamide; dronedarone; E-7070 of Eisai(N-(3-chloro-1H-indol-7-yl)-1,4-benzene-disulfonamide); EF-7412 ofSchwartz Pharma(N-3-[4-[4-(tetrahydro-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)butyl]-1-piperazinyl]phenyl]ethanesulfonamide);fenquizone; furosemide; glibenclamide; gliclazide; glimepiride;glipentide; glipizide; gliquidone; glisolamide; GW-8510 of GlaxoSmithKline(4-[[(6,7-dihydro-7-oxo-8H-pyrrolo[2,3-g]benzothiazol-8-ylidene)methyl]amino]-N-2-pyridinylbenzenesulfonamide);GYKI-16638 of Ivax(N-[4-[2-[[2-(2,6-dimethoxyphenoxy)-1-methylethyl]methylamino]ethyl]phenyl]methanesulfonamide);HMR-1098of Aventis(5-chloro-2-methoxy-N-[2-[4-methoxy-3-[[[(methylamino)thioxomethyl]amino]sulfonyl]phenyl]ethyl]benzamide);hydrochlorothiazide; ibutilide; indapamide; IS-741 of Ishihara(N-[2-[(ethylsulfonyl)amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanecarboxamide); JTE-522of Japan Tobacco(4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide);KCB-328 of Chugai(N-[3-amino-4-[2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]ethoxy]phenyl]methanesulfonamide);KT2-962 of Kotobuki (3-[4-[[(4-chlorophenyl)sulfonyl]amino]butyl]-6-(1-methylethyl)-1-azulene sulfonic acid);levosulpiride; LY-295501(N-[[(3,4-dichlorophenyl)amino]carbonyl]-2,3-dihydro-5-benzofuransulfonamide)and LY-404187 (N-2-(4-(4-cyanophenyl)phenyl)propyl-2-propanesulfonamide)of Eli Lilly; metolazone; naratriptan; nimesulide; NS-49 of Nippon((R)-N-[3-(2-amino-1-hydroxyethyl)-4-fluorophenyl]methanesulfonamide);ONO-8711 of Ono((5Z)-6-[(2R,3S)-3-[[[(4-chloro-2-methylphenyl)sulfonyl]amino]methyl]bicyclo[2.2.2]oct-2-yl]-5-hexenoicacid); piretamide; PNU-103657 of Pharmacia(1-[5-methanesulfonamidoindol-2-ylcarbonyl]-4-(N-methyl-N-(3-(2-methylpropyl)-2-pyridinyl)amino)piperidine);polythiazide; ramatroban; RO-61-1790 of Hoffmann LaRoche(N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-methyl-2-pyridinesulfonamide);RPR-130737(4-hydroxy-3-[2-oxo-3(S)-[5-(3-pyridyl)thiophen-2-ylsulfonamido]pyrrolidin-1-ylmethyl]benzamide)and RPR-208707 of Aventis; S-18886(3-[(6-(4-chlorophenylsulfonylamino)-2-methyl-5,6,7,8-tetrahydronaphth]-1-yl)propionicacid) and S-32080(3-[6-(4-chlorophenylsulfonylamido)-2-propyl-3-(3-pyridyl-methyl)-5,6,7,8-tetrahydronaphthalen-1-yl]propionicacid) of Servier; S-36496 of Kaken(2-sulfonyl-[N-(4-chlorophenyl)sulfonylamino-butyl-N-[(4-cyclobutylthiazol-2-yl)ethenylphenyl-3-yl-methyl]]aminobenzoicacid); sampatrilat; SB-203208 of Glaxo SmithKline (L-phenylalanine,b-methyl-,(4aR,6S,7R,7aS)-4-(aminocarbonyl)-7-[[[[[(2S,3S)-2-amino-3-methyl-1-oxopentyl]amino]sulfonyl]acetyl]amino]-7-carboxy-2,4a,5,6,7,7a-hexahydro-2-methyl-1H-cyclopenta[c]pyridin-6-ylester, (bS)-); SE-170 of DuPont(2-(5-amidino-1H-indol-3-yl)N-[2′-(aminosulfonyl)-3-bromo(1,1′-biphenyl)-4-yl]acetamide);sivelestat; SJA-6017 of Senju(N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal); SM-19712 of Sumitomo(4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl]benzenesulfonamide);sonepiprazole; sotalol; sulfadiazine; sulfaguanole; sulfasalazine;sulpiride; sulprostone; sumatriptan; T-614 of Toyama(N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide);T-138067(2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide)and T-900607(2,3,4,5,6-pentafluoro-N-(3-ureido-4-methoxyphenyl)benzenesulfonamide)of Tularik; TAK-661 of Takeda(2,2-dimethyl-3-[[7-(1-methylethyl)[1,2,4]triazolo[1,5-b]pyridazin-6-yl]oxy]-1-propanesulfonamide);tamsulosin; tezosentan; tipranavir; tirofiban; torasemide;trichloromethiazide; tripamide; valdecoxib; veralipride; xipamide; Z-335of Zeria (2-[2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]aceticacid); zafirlukast; zonisamide; and salts thereof.

[0039] In a preferred embodiment, the aminosulfonyl-comprising drug is aselective COX-2 inhibitory drug of low water solubility. Suitableselective COX-2 inhibitory drugs are compounds having the formula (IV):

[0040] wherein:

[0041] A is a substituent selected from partially unsaturated orunsaturated heterocyclyl and partially unsaturated or unsaturatedcarbocyclic rings, preferably a heterocyclyl group selected frompyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl andpyridazinonyl groups;

[0042] X is O, S or CH₂;

[0043] n is 0 or 1;

[0044] R¹ is at least one substituent selected from heterocyclyl,cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at asubstitutable position with one or more radicals selected from alkyl,haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,alkylsulfinyl, halo, alkoxy and alkylthio;

[0045] R² is an NH₂ group;

[0046] R³ is one or more radicals selected from hydrido, halo, alkyl,alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy,alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl,heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl,alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl,aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl,aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl andN-alkyl-N-arylaminosulfonyl, R³ being optionally substituted at asubstitutable position with one or more radicals selected from alkyl,haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,alkylsulfinyl, halo, alkoxy and alkylthio; and

[0047] R⁴ is selected from hydrido and halo.

[0048] Particularly suitable selective COX-2 inhibitory drugs arecompounds having the formula (V):

[0049] where R⁴ is hydrogen or a C₁₋₄ alkyl or alkoxy group, X is N orCR⁵ where R⁵ is hydrogen or halogen, and Y and Z are independentlycarbon or nitrogen atoms defining adjacent atoms of a five- tosix-membered ring that is unsubstituted or substituted at one or morepositions with oxo, halo, methyl or halomethyl groups. Preferred suchfive- to six-membered rings are cyclopentenone, furanone,methylpyrazole, isoxazole and pyridine rings substituted at no more thanone position.

[0050] Illustratively, compositions of the invention are suitable forcelecoxib, deracoxib, valdecoxib and JTE-522, more particularlycelecoxib and valdecoxib.

[0051] The invention is illustrated herein with particular reference tocelecoxib, and it will be understood that any drug of low watersolubility that comprises an aminosulfonyl functional group and/or iscapable of reacting with a polyethylene glycol or a polyethylene glycoldegradation product to form an addition compound can, if desired, besubstituted in whole or in part for celecoxib in compositions hereindescribed.

[0052] Where the drug is celecoxib, the composition typically comprisescelecoxib in a therapeutically and/or prophylactically effective totalamount of about 10 mg to about 1000 mg, preferably about 10 mg to about400 mg, and more preferably about 100 mg to about 200 mg, per dose unit.Where the drug is a selective COX-2 inhibitory drug other thancelecoxib, the amount of the drug per dose unit is therapeuticallyequivalent to about 10 mg to about 1000 mg of celecoxib.

[0053] Where the subject is a child or a small animal (e.g., a dog), forexample, an amount of celecoxib relatively low in the typical range ofabout 10 mg to about 1000 mg is likely to be consistent with therapeuticeffectiveness. Where the subject is an adult human or a large animal(e.g., a horse), therapeutic effectiveness is likely to require doseunits containing a relatively greater amount of celecoxib. For an adulthuman, a therapeutically effective amount of celecoxib per dose unit ina composition of the present invention is typically about 50 mg to about400 mg. Especially preferred amounts of celecoxib per dose unit areabout 100 mg to about 200 mg, for example about 100 mg or about 200 mg.

[0054] For other selective COX-2 inhibitory drugs, an amount of the drugper dose unit can be in a range known to be therapeutically effectivefor such drugs. Preferably, the amount per dose unit is in a rangeproviding therapeutic equivalence to celecoxib in the dose rangesindicated immediately above.

[0055] Form of Compositions of the Invention

[0056] Compositions of the present invention are preferably in the formof a concentrated solution that may or may not be encapsulated as adiscrete article. If encapsulated, preferably a single such article or asmall plurality (up to about 10, more preferably no more than about 4)of such articles is sufficient to provide the daily dose. Alternatively,compositions of the present invention are in the form of a concentratedimbibable liquid. The phrase “imbibable liquid” is used herein to referto an unencapsulated substantially homogeneous flowable mass, such as asolution or solution/suspension, administered orally and swallowed inliquid form and from which single dose units are measurably removable.The term “substantially homogeneous” with reference to a pharmaceuticalcomposition that comprises several components means that the componentsare sufficiently mixed such that individual components are not presentas discrete layers and do not form concentration gradients within thecomposition.

[0057] A particular dose unit can be selected to accommodate the desiredfrequency of administration used to achieve a specified daily dose. Forexample, a daily dosage amount of 400 mg can be accommodated byadministration of one 200 mg dose unit, or two 100 mg dose units, twicea day. The amount of the composition that is administered and the dosageregimen for treating the condition or disorder will depend on a varietyof factors, including the age, weight, sex and medical condition of thesubject, the nature and severity of the condition or disorder, the routeand frequency of administration, and the particular drug selected, andthus may vary widely. It is contemplated, however, that for mostpurposes a once-a-day or twice-a-day administration regimen provides thedesired therapeutic efficacy.

[0058] A composition of the invention comprises anaminosulfonyl-comprising drug of low water solubility, at least aportion of which is in dissolved or solubilized form in a solvent liquidsuitable for oral administration.

[0059] The solvent liquid comprises at least one pharmaceuticallyacceptable polyethylene glycol as a solvent, at least onepharmaceutically acceptable free radical-scavenging antioxidant andoptionally one or more additional components, including pharmaceuticallyacceptable excipients. The term “excipient” herein means any substance,not itself a therapeutic agent, used as a carrier or vehicle fordelivery of a therapeutic agent to a subject or added to apharmaceutical composition to improve its handling, storage,disintegration, dispersion, dissolution, release or organolepticproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule suitable for oraladministration. Excipients can include, by way of illustration and notlimitation, diluents, disintegrants, dispersants, binding agents,adhesives, wetting agents, lubricants, glidants, crystallizationinhibitors, stabilizers, substances added to mask or counteract adisagreeable taste or odor, flavors, dyes, fragrances, preservatives,and substances added to improve appearance of the composition.

[0060] Such optional additional components should be physically andchemically compatible with the other ingredients of the composition andshould not be deleterious to the recipient. Importantly, some of theabove-listed classes of excipients overlap each other. Compositions ofthe present invention can be adapted for administration by any suitableoral route by selection of appropriate solvent liquid components and adosage of the drug effective for the treatment intended. Accordingly,components employed in the solvent liquid can themselves be solids,semi-solids, liquids, or combinations thereof.

[0061] An imbibable composition of the invention can be in the form of,for example, a solution, a solution/suspension, an elixir, a syrup, orany other liquid form reasonably adapted for oral administration. Suchcompositions can also comprise excipients selected from, for example,emulsifying and suspending agents, sweetening and flavoring agents,surfactants and co-surfactants.

[0062] Alternatively, as described in detail below, a composition of thepresent invention can be prepared in the form of discrete unit dosearticles, for example, capsules having a wall that illustrativelycomprises gelatin and/or a turbidity-decreasing polymer such as HPMC,each capsule containing a liquid composition comprising a predeterminedamount of drug in a solvent liquid. The liquid composition within thecapsule is released by breakdown of the wall on contact withgastrointestinal fluid. The particular mechanism of capsule wallbreakdown is not important and can include such mechanisms as erosion,degradation, dissolution, etc.

[0063] Compositions of the invention can be prepared by any suitablemethod of pharmacy that includes the step of bringing into associationthe drug and the components of the solvent liquid. The polyethyleneglycol solvent, the free radical-scavenging antioxidant and the other,optional, components of the solvent liquid can be mixed first, prior toaddition of the drug; alternatively, the drug can be mixed with thesolvent before addition of other components. Order of addition isgenerally not critical, but it is typically preferred to add the drug tothe solvent liquid after adding the antioxidant. In general, celecoxibcompositions of the invention are prepared by uniformly and intimatelyadmixing celecoxib with a solvent liquid in such a way that at least aportion, preferably substantially all, of the celecoxib is dissolved orsolubilized in the solvent liquid; and then, if desired, encapsulatingthe resulting solution or solution/suspension, for example in hard orsoft capsules.

[0064] A preferred embodiment of the invention is a compositioncomprising a therapeutically effective amount of anaminosulfonyl-comprising drug of low water solubility, for examplecelecoxib or valdecoxib, substantially completely dissolved in a solventliquid comprising at least one pharmaceutically acceptable polyethyleneglycol and at least one pharmaceutically acceptable freeradical-scavenging antioxidant. In this embodiment, substantially nopart of the drug is present in solid particulate form. Compositions ofthis embodiment can be formulated either in an imbibable or discretedosage form (e.g., encapsulated). Preferably, concentrated solutions ofthis embodiment have a drug concentration of about 10% to about 75%,more preferably about 20% to about 75%, by weight of the composition.

[0065] Solvent

[0066] Any pharmaceutically acceptable polyethylene glycol (PEG) can beused as a solvent in a composition of the invention. Preferably, the PEGhas an average molecular weight of about 100 to about 10,000, and morepreferably about 100 to about 1,000. Still more preferably, the PEG isof liquid grade. Non-limiting examples of PEGs that can be used insolvent liquids of this invention include PEG-200, PEG-350, PEG-400,PEG-540 and PEG-600. See for example Flick (1998): Industrial SolventsHandbook, 5th ed., Noyes Data Corporation, Westwood, N.J., p. 392. Apresently preferred PEG has an average molecular weight of about 375 toabout 450, as exemplified by PEG-400.

[0067] As pointed out hereinabove, PEGs such as PEG-400 have manydesirable properties as solvents for poorly water-soluble drugs. In thecase of celecoxib, for example, the drug can be dissolved or solubilizedat a very high concentration in PEG-400, enabling formulation of atherapeutically effective dose in a very small volume of solvent liquid.This is especially important where the resulting solution is to beencapsulated, as capsules of a size convenient for swallowing can beprepared containing a therapeutically effective dose even of a drug suchas celecoxib having a relatively high dose requirement for efficacy.

[0068] However, the present inventors encountered an unexpected problemwhen celecoxib was formulated in dissolved or solubilized form inPEG-400. During storage of a solution formulation of celecoxib inPEG-400, one or more impurities were generated. These impurities weretraced to reaction of the celecoxib not with PEG-400 itself but with abreakdown product of PEG-400. Without being bound by theory, it isbelieved that the breakdown product that reacts with celecoxib isethylene oxide. Products of the reaction include addition compoundshaving chemical structures that have now been determined and aredisclosed hereinbelow. It is contemplated that any drug compound havingan aminosulfonyl functional group has a potential to react with apolyethylene glycol breakdown product in a similar way.

[0069] The problem of chemical instability of such a drug in apolyethylene glycol solvent, or indeed of any drug that can react withpolyethylene glycol or a breakdown product thereof to form an additioncompound, has now been solved. According to the present invention,presence of a free radical-scavenging antioxidant in the solvent liquidgreatly enhances chemical stability of the drug.

[0070] Free Radical-Scavenging Antioxidant

[0071] Certain drugs present in aqueous preparations are known to besusceptible to oxidative degradation, particularly in the presence ofoxygen. Hydrogen peroxide, for example, is a known free radicalgenerator that can produce free radicals that interact with drugs insuch preparations so as to cause drug degradation. Antioxidants havebeen used in the art to limit such peroxide-mediated drug degradation.Generally, in such a situation, antioxidants act by providing electronsand easily available hydrogen atoms that are accepted more readily bythe free radicals than are those of the drug being protected. See Anselet al. (1995): Pharmaceutical Dosage Forms and Drug Delivery Systems,6th Edition, page 117.

[0072] The problem faced by the present inventors differs from the abovesituation in at least two ways. First, according to the present problemit is believed that it is polyethylene glycol, not the drug, that isdirectly degraded by free radicals. Second, there is strong evidence tosuggest that the degradation mechanism is not dependent upon peroxide(i.e., the polyethylene glycol degradation proceeds by anoxygen-independent mechanism).

[0073] Surprisingly, we have now discovered that the presence of a smallamount of a free-radical scavenging antioxidant in a composition of theinvention greatly improves chemical stability of the drug. This findingis quite different from above-described situations where antioxidantshave previously been used to prevent drug degradation. Without beingbound by theory, it is believed that a free radical-scavengingantioxidant inhibits, slows or delays polyethylene glycol degradation,thereby limiting or inhibiting chemical interaction between polyethyleneglycol degradation products and the drug.

[0074] Therefore, a composition of the present invention comprises atleast one pharmaceutically acceptable free radical-scavengingantioxidant. A free radical-scavenging antioxidant is to be contrastedwith a “non-free radical-scavenging antioxidant”, i.e., an antioxidantthat does not possess free radical-scavenging properties. Non-limitingillustrative examples of suitable free radical-scavenging antioxidantsinclude α-tocopherol (vitamin E), ascorbic acid (vitamin C) and saltsthereof including sodium ascorbate and ascorbic acid palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), fumaricacid and salts thereof, hypophosphorous acid, malic acid, alkylgallates, for example propyl gallate, octyl gallate and lauryl gallate,sodium thiosulfate, sodium sulfite, sodium bisulfite and sodiummetabisulfite. Preferred free radical-scavenging antioxidants are alkylgallates, vitamin E, BHA and BHT. More preferably the at least one freeradical-scavenging antioxidant is propyl gallate.

[0075] One or more free radical-scavenging antioxidants are present incompositions of the invention in a total amount effective tosubstantially reduce formation of an addition compound, typically in atotal amount of about 0.01% to about 5%, preferably about 0.01% to about2.5%, and more preferably about 0.01% to about 11%, by weight of thecomposition.

[0076] Other Excipients

[0077] Compositions of the invention optionally contain pharmaceuticallyacceptable excipients other than polyethylene glycol and freeradical-scavenging antioxidants. In the case of a solution composition,for example, such excipients can include co-solvents, sweeteners,crystallization inhibitors, preservatives, dispersants, emulsifyingagents, etc. Through selection and combination of excipients,compositions can be provided exhibiting improved performance withrespect to drug concentration, dissolution, dispersion, emulsification,efficacy, flavor, patient compliance and other properties.

[0078] A composition, particularly a solution composition, of theinvention optionally comprises one or more pharmaceutically acceptableco-solvents. Non-limiting examples of suitable co-solvents includeadditional glycols, alcohols, for example ethanol and n-butanol; oleicand linoleic acid triglycerides, for example soybean oil;caprylic/capric triglycerides, for example Miglyol™ 812 of Huls;caprylic/capric mono- and diglycerides, for example Capmul™ MCM ofAbitec; polyoxyethylene caprylic/capric glycerides such aspolyoxyethylene (8) caprylic/capric mono- and diglycerides, for exampleLabrasol™ of Gattefosse; propylene glycol fatty acid esters, for examplepropylene glycol laurate; polyoxyethylene (35) castor oil, for exampleCremophorm EL of BASF; polyoxyethylene glyceryl trioleate, for exampleTagat™ TO of Goldschmidt; lower alkyl esters of fatty acids, for exampleethyl butyrate, ethyl caprylate and ethyl oleate; and water.

[0079] A composition, particularly a solution composition, of theinvention optionally comprises a pharmaceutically acceptable fatty acidand a pharmaceutically acceptable organic amine (also referred to hereinas a “fatty acid/organic amine pair”) in total and relative amounts suchthat the composition is finely self-emulsifiable in simulated gastricfluid. “Simulated gastric fluid” and its abbreviation “SGF”, as the termis used herein, describes an aqueous solution of 0.01M hydrochloric acidand 0. 15M sodium chloride, having a pH of about 2. Without being boundby theory, it is believed that a fatty acid/organic amine pair, whenpresent in a composition of the invention, promotes formation of chargedfine-emulsion droplets upon exposure of the composition to an aqueousmedium such as SGF.

[0080] Whether a composition is “finely self-emulsifiable” in SGF asdefined herein can illustratively be determined according to Test I.

[0081] Test I:

[0082] A. A 400 μl aliquot of a test composition is placed into ascrew-top, side-arm vessel containing 20 ml SGF (maintained at 37° C.throughout the test) to form a test liquid.

[0083] B. The test liquid is mildly agitated at 75 rpm for 2 minutesusing an orbital shaker, to permit emulsification.

[0084] C. A 5-50 μl aliquot of the test liquid is withdrawn through theside-arm using a pipette and is discharged from the pipette into asampling vessel.

[0085] D. A pump (e.g., model RHOCKC-LF, Fluid Metering Inc., Syosset,N.Y.) is used to pull the test liquid from the sampling vessel through acombination scattering/obscuration sensor (e.g., LE400-0.5, ParticleSizing Systems, Santa Barbara, Calif.) at a rate of 1 ml/minute for aperiod of 1 minute.

[0086] E. Emulsion particles are counted individually by lightscattering in the size (i.e., diameter) range from 0.5 to 1 μm and bylight obscuration in the size range above 1 μm, using the vendor'ssoftware (e.g., Version 1.59).

[0087] F. A plot is prepared of number (i.e., unweighted) or volume(i.e., weighted) of emulsion particles versus particle diameter.

[0088] G. Integration of the plot, accounting for all dilutions, isperformed to estimate total number or volume of emulsion particlespresent in the test liquid large enough to be detected by the sensor.

[0089] H. If Test I results in about 25% or more, by volume, of emulsionparticles having a diameter of 1 μm or less, the test composition isdeemed to be finely self-emulsifiable.

[0090] Preferred fatty acids have a saturated or unsaturated C₆₋₂₄carbon chain. Non-limiting examples of suitable fatty acids includeoleic acid, octanoic acid, caproic acid, caprylic acid, capric acid,eleostearic acid, lauric acid, myristic acid, palmitic acid, stearicacid, icosanoic acid, elaidic acid, linoleic acid, linolenic acid,eicosapentaenoic acid and docosahexaenoic acid. Oleic acid is anespecially preferred fatty acid.

[0091] Preferred organic amines have a C₂₋₈ carbon chain with one or twoamine groups. More preferably, organic amines can be selected from C₂₋₈alkyl amines, alkylene diamines, alkanol amines, alkylalkanol amines,glycol ether amines and aryl amines. Non-limiting examples of suitableorganic amines include monoethanolamine, diethanolamine,triethanolamine, dimethylaminoethanol, tromethamine, etc. Particularlypreferred organic amines are tertiary amines, for exampletriethanolamine and dimethylaminoethanol.

[0092] Preferably, if present, a fatty acid/organic amine pair isselected (as to both type and amount of each component) such that when acomposition of the invention is subjected to Test I, at least about50%and more preferably at least about 75%, by volume, of the emulsionparticles counted have a diameter of about 1 μm or less. It isespecially preferred that a substantial portion by volume of theemulsion particles counted, more preferably at least about 75%, stillmore preferably at least about 85%, and most preferably at least about90%, have a diameter of about 0.5 μm or less.

[0093] A preferred mole ratio of fatty acid to amine group(s) in theorganic amine is about 5:1 to about 1:100, more preferably about 3:1 toabout 1:50, and still more preferably about 2:1 to about 1:10, forexample about 1:1. Preferably, if present, the fatty acid and organicamine are collectively present in an amount of about 1% to about 50%,more preferably about 2% to about 30%, and still more preferably about5% to about 15%, by weight of the composition.

[0094] It is believed, without being bound by theory, that a finelyself-emulsifiable solution composition of the invention, particularlyone having a fatty acid/organic amine pair as described above, willprovide the drug in a form that is especially rapidly absorbable in thegastrointestinal tract.

[0095] In a solution composition of the invention, the drug, even whenfinely emulsified, can, upon exposure to the aqueous environment of thegastrointestinal tract, precipitate and agglomerate in a solid,typically crystalline, particulate form. Such precipitation and/orcrystallization can adversely impact any rapid-onset benefits obtainedby administering a drug in dissolved form, because a drug that hasreverted to a crystalline form must undergo the process of dissolutionprior to absorption.

[0096] Therefore, preferred compositions further comprise acrystallization inhibitor, also referred to herein as aturbidity-decreasing polymer. We have discovered that certain polymerscan substantially inhibit precipitation and/or crystallization of apoorly water-soluble drug, when a solution of the drug in asubstantially non-aqueous solvent is exposed to SGF. Accordingly,compositions of the present invention preferably comprise aturbidity-decreasing polymer. The polymer can be a cellulosic ornon-cellulosic polymer and is preferably substantially water-soluble.

[0097] It will be understood that certain polymers are more effective atinhibiting precipitation and/or crystallization of a selected poorlywater soluble drug than others, and that not all polymers inhibitprecipitation and/or crystallization as described herein of every poorlywater-soluble drug. Whether a particular polymer is useful as acrystallization inhibitor for a particular poorly water soluble drugaccording to the present invention can be readily determined by one ofordinary skill in the art, for example according to Test II.

[0098] Test II:

[0099] A. A suitable amount of the drug is dissolved in a solvent (e.g.,ethanol, dimethyl sulfoxide or, where the drug is an acid or base,water) to obtain a concentrated drug solution.

[0100] B. A volume of water or buffered solution with a fixed pH isplaced in a first vessel and maintained at room temperature.

[0101] C. An aliquot of the concentrated drug solution is added to thecontents of the first vessel to obtain a first sample solution having adesired target drug concentration. The drug concentration selectedshould be one which produces substantial precipitation and consequentlyhigher apparent absorbance (i.e., turbidity) than a saturated solutionhaving no such precipitation.

[0102] D. A test polymer is selected and, in a second vessel, thepolymer is dissolved in water or a buffered solution with a fixed pH(identical in composition, pH and volume to that used in step C) in anamount sufficient to form a 0.25%-2% w/w polymer solution.

[0103] E. To form a second sample solution, an aliquot of theconcentrated drug solution prepared in step A is added to the polymersolution in the second vessel to form a sample solution having a finaldrug concentration equal to that of the first sample solution.

[0104] F. At 60 minutes after preparation of both sample solutions,apparent absorbance (i.e., turbidity) of each sample solution ismeasured using light having a wavelength of 650 nm;

[0105] G. If the turbidity of the second sample solution is less thanthe turbidity of the first sample solution, the test polymer is deemedto be a “turbidity-decreasing polymer” and is useful as acrystallization inhibitor for the test drug.

[0106] A technician performing Test II will readily find a suitablepolymer concentration for the test within the polymer concentrationrange provided above, by routine experimentation. In a particularlypreferred embodiment, a concentration of the polymer is selected suchthat when Test II is performed, the apparent absorbance of the secondsample solution is not greater than about 50% of the apparent absorbanceof the first sample solution.

[0107] In another embodiment, compositions of the invention comprise acrystallization inhibitor comprising at least one cellulosic polymer.Preferred cellulosic polymers are selected from HPMC, methylcellulose,ethylcellulose, sodium carboxymethylcellulose andhydroxypropylcellulose. More preferably, the at least one cellulosicpolymer is selected from cellulosic polymers having at least a portionof substitutable hydroxyl groups substituted with methoxyl and/orhydroxypropoxyl groups. Still more preferably, the at least onecellulosic polymer is HPMC.

[0108] HPMC useful as a crystallization inhibitor according to theinvention preferably has a viscosity, 2% in water, of about 100 to about20,000 cP. HPMCs vary in the degree of substitution of availablehydroxyl groups on the cellulosic backbone by methoxyl groups and byhydroxypropoxyl groups. With increasing hydroxypropoxyl substitution,the resulting HPMC becomes more hydrophilic in nature. It is preferredto use HPMC having about 15% to about 35%, more preferably about 19% toabout 30%, and most preferably about 19% to about 24%, methoxylsubstitution, and having about 3% to about 15%, more preferably about 4%to about 12%, and most preferably about 7% to about 12%, hydroxypropoxylsubstitution.

[0109] Suitable HPMCs that are relatively hydrophilic in nature areillustratively available under the brand names Methocel™ of Dow ChemicalCo. and Metolose™ of Shin-Etsu Chemical Co.

[0110] An illustrative presently preferred HPMC is one with substitutiontype 2208, denoting about 19% to about 24% methoxyl substitution andabout 7% to about 12% hydroxypropoxyl substitution, and with a nominalviscosity, 2% in water, of about 4000 cP.

[0111] Surprisingly, it has been found that the crystallizationinhibitor need not be a component of the solvent liquid. Optionally, acrystallization inhibitor such as HPMC can be a component of a capsulewall wherein a solution composition of the invention is encapsulated. Inone embodiment, substantially no HPMC or other crystallization inhibitoris present in the solvent liquid but the capsule wall comprises HPMC.The capsule wall can even consist predominantly of HPMC.

[0112] If present, the crystallization inhibitor is preferably presentin a total amount sufficient to substantially inhibit drugcrystallization and/or precipitation upon dilution of the composition inSGF. An amount sufficient to “substantially inhibit drug crystallizationand/or precipitation” herein means an amount sufficient to prevent,slow, inhibit or delay precipitation of drug from solution and/or toprevent, slow, inhibit or delay formation of crystalline drug particlesfrom dissolved drug particles. For practical purposes, whether an amountof crystallization inhibitor in a given test composition is sufficientto substantially inhibit drug crystallization and/or precipitation canbe determined according to Test III, which can also be used to determinewhether a particular polymer component is useful as a crystallizationinhibitor in a particular composition of the invention.

[0113] Test III:

[0114] A. A volume of a test composition, either in unencapsulated orencapsulated form, having a polymer component is placed in a volume ofSGF to form a mixture having a fixed ratio of about 1 g to about 2 g ofthe composition per 100 ml of SGF.

[0115] B. The mixture is maintained at a constant temperature of about37° C. and is stirred using type II paddles (U.S. Pat. No. 24) at a rateof 75 rpm for a period of 4 hours.

[0116] C. At one or more time-points after at least about 15 minutes ofstirring but before about 4 hours of stirring, an aliquot of the mixtureis drawn and filtered, for example through a non-sterile Acrodisc™syringe filter with a 0.8 μm Versaporm membrane.

[0117] D. Filtrate is collected in a vessel.

[0118] E. Drug concentration in the filtrate is measured using highperformance liquid chromatography (HPLC).

[0119] F. The test is repeated identically with a comparativecomposition that is substantially similar to the test composition exceptthat it lacks the polymer component. Where the polymer component in thetest composition is present in the solvent liquid, it is replaced in thecomparative composition by polyethylene glycol solvent. Where thepolymer component in the test composition is present in a capsule wall,it is replaced in the comparative composition with gelatin.

[0120] G. If the drug concentration in the filtrate resulting from thetest composition is greater than that in the filtrate resulting from thecomparative composition, the polymer component present in the testcomposition is deemed to substantially inhibit crystallization and/orprecipitation of the drug in SGF.

[0121] A crystallization inhibitor such as HPMC, when present in thesolvent liquid, is generally present in a total amount of about 1% toabout 20%, preferably about 1% to about 15%, and most preferably about1% to about 10%, by weight of the solvent liquid. Typically, the higherthe drug concentration in the composition, the more of the cellulosicpolymer will be required to provide a crystallization-inhibiting effect.Generally, the crystallization inhibitor, if present, and the drug arepresent in a ratio of about 1:100 to about 1:1, preferably about 1:50 toabout 1:1 and more preferably about 1:25 to about 1:1, by weight.

[0122] A composition of the invention optionally comprises one or morepharmaceutically acceptable sweeteners. Non-limiting examples ofsuitable sweeteners include mannitol, propylene glycol, sodiumsaccharin, acesulfame K, neotame and aspartame. Alternatively or inaddition, a viscous sweetener such as sorbitol solution, syrup (sucrosesolution) or high-fructose corn syrup can be used and, in addition tosweetening effects, can also be useful to increase viscosity and toretard sedimentation. Use of sweeteners is especially advantageous inimbibable compositions of the invention, as these can be tasted by thesubject prior to swallowing. An encapsulated composition does nottypically interact with the organs of taste in the mouth and use of asweetener is normally unnecessary.

[0123] A composition of the invention optionally comprises one or morepharmaceutically acceptable preservatives other than freeradical-scavenging antioxidants. Non-limiting examples of suitablepreservatives include benzalkonium chloride, benzethonium chloride,benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate, thimerosal, etc.

[0124] A composition of the invention optionally comprises one or morepharmaceutically acceptable wetting agents. Surfactants, hydrophilicpolymers and certain clays can be useful as wetting agents to aid indissolution and/or dispersion of a hydrophobic drug such as celecoxib.Non-limiting examples of suitable surfactants include benzalkoniumchloride, benzethonium chloride, cetylpyridinium chloride, dioctylsodium sulfosuccinate, nonoxynol 9, nonoxynol 10, octoxynol 9,poloxamers, polyoxyethylene (8) caprylic/capric mono- and diglycerides(e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil,polyoxyethylene (20) cetostearyl ether, polyoxyethylene (40)hydrogenated castor oil, polyoxyethylene (10) oleyl ether,polyoxyethylene (40) stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80 (e.g., Tween™ 80 of ICI), propyleneglycol laurate (e.g., Lauroglycol™ of Gattefosse), sodium laurylsulfate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, tyloxapol, and mixtures thereof.

[0125] Additionally, compositions of the invention optionally compriseone or more pharmaceutically acceptable buffering agents, flavoringagents, colorants, stabilizers and/or thickeners. Buffers can be used tocontrol pH of a formulation and can thereby modulate drug solubility.Flavoring agents can enhance patient compliance by making thecomposition more palatable, particularly in the case of an imbibablecomposition, and colorants can provide a product with a more aestheticand/or distinctive appearance. Non-limiting examples of suitablecolorants include D&C Red No. 33, FD&C Red No. 3, FD&C Red No. 40, D&CYellow No. 10, and C Yellow No. 6.

[0126] Solution/Suspension Compositions

[0127] In one embodiment, the solvent liquid, depending on theparticular components present therein, is suitable to maintain a firstportion of drug in solution to provide a therapeutically effectiverapid-onset dose while also maintaining a second portion of the drugundissolved but in suspension. The suspended portion typically providesless immediate release of the drug and so can extend the duration oftherapeutic effect, although such extended duration is not a requirementof this embodiment of the invention.

[0128] Therefore, according to this embodiment a composition is providedcomprising a therapeutically effective amount of a poorly water-solubleaminosulfonyl-comprising drug, in part dissolved and in part dispersedin a solvent liquid that comprises at least one pharmaceuticallyacceptable polyethylene glycol and at least one pharmaceuticallyacceptable free radical-scavenging antioxidant. In this embodiment, partof the drug is in solution and part is in suspension.

[0129] Preferably, the components of the solvent liquid are selectedsuch that at least about 15% by weight of the drug is in dissolved orsolubilized form in the solvent liquid. One way of modifying a solventliquid to increase the amount of the poorly water solubleaminosulfonyl-comprising drug in suspension as opposed to solution is toadd water in an amount necessary to give the required reduction insolubility of the drug in the solvent liquid.

[0130] Depending on the relative importance of rapid onset and sustainedaction for the indication for which the drug is being administered, therelative proportions of dissolved and suspended drug can be variedsignificantly. For example, for acute pain indications, about 50% of thedrug can be in solution and about 50% of the drug can be dispersed inparticulate form. Alternatively, for indications demanding longer actingtherapeutic effectiveness, illustratively about 20% of the drug can bein solution and about 80% of the drug can be dispersed in particulateform.

[0131] The particulate form of the drug can be generated mechanically,for example by milling or grinding, or by precipitation from solution.Particles formed directly from such processes are described herein as“primary particles” and can agglomerate to form secondary aggregateparticles. The term “particle size” as used herein refers to size, inthe longest dimension, of primary particles, unless the context demandsotherwise. Particle size is believed to be an important parameteraffecting the clinical effectiveness of celecoxib and other drugs of lowwater solubility.

[0132] Particle size can be expressed as the percentage of totalparticles that have a diameter smaller than a given reference diameter.For example, a useful parameter is “D₉₀ particle size”. By definition,in a batch of a drug that has a D₉₀ particle size of 60 μm, 90% of theparticles, by volume, have a diameter less than 60 μm. For practicalpurposes a determination of D₉₀ based on 90% by weight rather than byvolume is generally suitable.

[0133] Compositions of this embodiment preferably have a distribution ofsuspended drug particle sizes such that D₉₀ of the particles, in theirlongest dimension, is about 0.5 μm to about 200 μm, preferably about 0.5μm to about 75 μm, and more preferably about 0.5 μm to about 25 μm. Forexample, where the drug is celecoxib, a decrease in particle size inaccordance with this embodiment of the invention generally improves drugbioavailability. In addition or alternatively, suspended celecoxibparticles in a composition of the invention preferably have a meanparticle size less than about 10 μm, more preferably about 0.1 μm toabout 10 μm, and most preferably about 0.5 μm to about 5 μm, for exampleabout 1 μm.

[0134] Compositions of this embodiment can optionally compriseadditional excipients such as crystallization inhibitors, dispersants,co-solvents, sweeteners, preservatives, emulsifying agents, etc., asdescribed above. Further, compositions of this embodiment can beformulated either in imbibable or discrete dosage form.

[0135] Additionally, certain excipients such as suspending agents,thickening agents and flocculating agents can be particularly usefulwhere suspended drug particles are desired, for example insolution/suspension compositions. Through selection and combination ofexcipients, solution/suspension compositions can be provided exhibitingimproved performance with respect to drug concentration, physicalstability, efficacy, flavor, and overall patient compliance.

[0136] Solution/suspension compositions of the invention optionallycomprise one or more pharmaceutically acceptable suspending agents.Suspending agents are used to impart increased viscosity and retardsedimentation. Suspending agents are of various classes includingcellulose derivatives, clays, natural gums, synthetic gums andmiscellaneous agents. Non-limiting examples of suspending agents thatcan be used in compositions of the present invention include acacia,agar, alginic acid, aluminum monostearate, attapulgite, bentonite,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carrageenan, carbomer, for example carbomer 910, dextrin,ethylmethylcellulose, gelatin, guar gum, BPMC, methylcellulose,ethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, kaolin, magnesium aluminum silicate,microcrystalline cellulose, microcrystalline cellulose withcarboxymethylcellulose sodium, powdered cellulose, silica gel, colloidalsilicon dioxide, locust bean gum, pectin, sodium alginate, propyleneglycol alginate, tamarind gum, tragacanth, xanthan gum, povidone,veegum, glycyrrhizin, pregelatinized starch, sodium starch glycolate andmixtures thereof.

[0137] In certain circumstances, it can be desirable to use flocculatingagents in solution/suspension compositions of the invention.Flocculating agents enable particles to link together in looseaggregates or flocs and include surfactants, hydrophilic polymers, claysand electrolytes. Non-limiting examples of suitable flocculating agentsinclude sodium lauryl sulfate, docusate sodium, benzalkonium chloride,cetylpyridinium chloride, polysorbate 80, sorbitan monolaurate,carboxymethylcellulose sodium, xanthan gum, tragacanth, methylcellulose,PEG, magnesium aluminum silicate, attapulgite, bentonite, potassiumdihydrogen phosphate, aluminum chloride, sodium chloride and mixturesthereof.

[0138] Discrete Dosage Forms

[0139] It has been found that the demands of a rapid-onset formulationare met surprisingly well by a preparation containing a solution orsolution/suspension of the present invention encapsulated as a discretedosage unit article. Therefore, another embodiment of the presentinvention is a concentrated composition, either a solution orsolution/suspension, wherein the composition is formulated as one ormore discrete dose units, for example soft or hard capsules.

[0140] Any suitable encapsulation material, for example gelatin or HPMC,can be used. As indicated hereinabove, HPMC can be an advantageousmaterial for use in the capsule wall because it can act as acrystallization inhibitor upon exposure of the composition togastrointestinal fluid. A polymer component such as HPMC is “present inthe capsule wall” or is a “capsule wall component” as described hereinif the polymer is (a) dispersed or mixed together with any other capsulewall component(s), (b) the only capsule wall component, or (c) presentas a coating on the outside or inside of the capsule wall.

[0141] In a presently preferred embodiment, a crystallization inhibitor,preferably a polymer having methoxyl and/or hydroxypropoxyl substitutionas described hereinabove, and more preferably HPMC, is present in thecapsule wall in a total amount of about 5% to substantially 100%, andpreferably about 15% to substantially 100%, by weight of the wall.

[0142] The crystallization inhibitor is preferably present in the wallin a total amount sufficient to substantially inhibit drugcrystallization and/or precipitation upon dissolution, dilution and/ordegradation of the composition in SGF. For practical purposes, whetheran amount of crystallization inhibitor present in the wall of a giventest composition is sufficient to substantially inhibit drugcrystallization and/or precipitation can be determined according to TestIV, which can also be used to determine whether a particular polymercomponent is useful as a crystallization inhibitor when present in thecapsule wall of a particular composition of the invention.

[0143] Test IV:

[0144] A. A volume of a solution or solution/suspension as describedherein above is enclosed in a capsule comprising a test polymer to forma test composition, and is placed in a volume of SGF to form a mixturehaving a fixed ratio of about 1 g to about 2 g of the composition per100 ml of SGF.

[0145] B. The mixture is maintained at a constant temperature of about37° C. and is stirred using type II paddles (U.S. Pat. No. 24) at a rateof 75 rpm for a period of 4 hours.

[0146] C. At one or more time-points after at least about 15 minutes ofstirring but before about 4 hours of stirring, an aliquot of the mixtureis drawn and filtered, for example through a non-sterile Acrodisc™syringe filter with a 0.8 μm Versapor™ membrane.

[0147] D. Filtrate is collected in a vessel.

[0148] E. Drug concentration in the filtrate is measured using highperformance liquid chromatography (HPLC).

[0149] F. The test is repeated identically with a comparativecomposition comprising a solution or solution/suspension that issubstantially similar to the solution or solution/suspension used inStep A but which is enclosed in a capsule comprising no crystallizationinhibitor (i.e. comprises no polymer or, if a polymer is present, it isa polymer such as gelatin which does not inhibit crystallization and/orprecipitation). The polymer component is replaced in the capsuleenclosing the comparative composition with gelatin.

[0150] G. If the drug concentration in the filtrate resulting from thetest composition is greater than that in the filtrate resulting from thecomparative composition, the polymer component present in the capsulewall of the test composition is deemed to be present in an amountsufficient to substantially inhibit crystallization and/or precipitationof the drug in SGF.

[0151] In addition to one or more such crystallization inhibitors, asuitable capsule wall can comprise any additional component useful inthe art such as gelatin, starch, carrageenan, sodium alginate,plasticizers, potassium chloride, coloring agents, etc. A suitablecapsule herein may have a hard or soft wall.

[0152] Preferably, one to about six, more preferably one to about four,and still more preferably one or two of such discrete dosage units perday provides a therapeutically effective dose of the drug.

[0153] Compositions of this embodiment are preferably formulated suchthat each discrete dosage unit contains about 0.3 ml to about 1.5 ml,more preferably about 0.3 ml to about 1 ml, for example about 0.8 ml orabout 0.9 ml, of solution or solution/suspension.

[0154] Concentrated solutions or solutions/suspensions can beencapsulated by any method known in the art including the plate process,vacuum process, or the rotary die process. See, for example, Ansel etal. (1995) in Pharmaceutical Dosage Forms and Drug Delivery Systems, 6thed., Williams & Wilkins, Baltimore, Md., pp. 176-182. By the rotary dieprocess, liquid encapsulation material, for example gelatin, flowingfrom an overhead tank is formed into two continuous ribbons by a rotarydie machine and brought together by twin rotating dies. Simultaneously,metered fill material is injected between ribbons at the same momentthat the dies form pockets of the ribbons. These pockets offill-containing encapsulation material are then sealed by pressure andheat, and the capsules are served from the machine.

[0155] Soft capsules can be manufactured in different shapes includinground, oval, oblong, and tube-shape, among others. Additionally, byusing two different ribbon colors, two-tone capsules can be produced.

[0156] Capsules that comprise HPMC are known in the art and can beprepared, sealed and/or coated, by way of non-limiting illustration,according to processes disclosed in the patents and publications listedbelow, each of which is individually incorporated herein by reference.

[0157] U.S. Pat. No. 4,250,997 to Bodenmann et al.

[0158] U.S. Pat. No. 5,264,223 to Yamamoto et al.

[0159] U.S. Pat. No. 5,756,123 to Yamamoto et al.

[0160] International Patent Publication No. WO 96/05812.

[0161] International Patent Publication No. WO 97/35537.

[0162] International Patent Publication No. WO 00/18377.

[0163] International Patent Publication No. WO 00/27367.

[0164] International Patent Publication No. WO 00/28976.

[0165] International Patent Publication No. WO 01/03676.

[0166] European Patent Application No.0 211 079.

[0167] European Patent Application No. 0 919 228.

[0168] European Patent Application No. 1 029 539.

[0169] Non-limiting illustrative examples of suitable HPMC-comprisingcapsules include XGel™ capsules of Bioprogress and Qualicaps™ ofShionogi.

[0170] Imbibable Dosage Forms

[0171] Another embodiment of the present invention is a concentratedcomposition, either a concentrated solution or a concentratedsolution/suspension, that can be directly imbibed or diluted with inertdiluents and/or other carriers and imbibed; such compositions of theinvention, whether diluted or not, are referred to for convenienceherein as “imbibable compositions”. Imbibable compositions can beprepared by any suitable method of pharmacy that includes the steps ofbringing into association the drug of low water solubility,illustratively celecoxib, and the solvent liquid. Where the drug iscelecoxib, compositions of this embodiment preferably contain about 40mg/ml to about 750 mg/ml, more preferably about 50 mg/ml to about 500mg/ml, still more preferably about 50 mg/ml to about 350 mg/ml, and mostpreferably, about 100 mg/ml to about 300 mg/ml, for example about 200mg/ml, of celecoxib.

[0172] In a further embodiment, solutions or solution/suspensions of theinvention are provided that are required to be diluted to provide adilution suitable for direct, imbibable administration. In thisembodiment, solutions or solution/suspensions of the present inventionare added, in a therapeutically effective dosage amount, to about 1 mlto about 20 ml of an inert liquid. Preferably solutions orsolution/suspensions of the present invention are added to about 2 ml toabout 15 ml, and more preferably to about 5 ml to about 10 ml, of inertliquid. The term “inert liquid” as used herein refers topharmaceutically acceptable, preferably palatable liquid carriers. Suchcarriers are typically aqueous. Examples include water, fruit juices,carbonated beverages, etc.

[0173] Utility of Compositions that Comprise a Selective COX-2Inhibitory Drug

[0174] In a preferred embodiment, compositions of the invention comprisean aminosulfonyl-comprising selective COX-2 inhibitory drug of low watersolubility. Compositions of this embodiment are useful in treatment andprevention of a very wide range of disorders mediated by COX-2,including but not restricted to disorders characterized by inflammation,pain and/or fever. Such compositions are especially useful asanti-inflammatory agents, such as in treatment of arthritis, with theadditional benefit of having significantly less harmful side effectsthan compositions of conventional nonsteroidal anti-inflammatory drugs(NSAIDs) that lack selectivity for COX-2 over COX-1. In particular, suchcompositions have reduced potential for gastrointestinal toxicity andgastrointestinal irritation including upper gastrointestinal ulcerationand bleeding, reduced potential for renal side effects such as reductionin renal function leading to fluid retention and exacerbation ofhypertension, reduced effect on bleeding times including inhibition ofplatelet function, and possibly a lessened ability to induce asthmaattacks in aspirin-sensitive asthmatic subjects, by comparison withcompositions of conventional NSAIDs. Thus compositions of the inventioncomprising a selective COX-2 inhibitory drug are particularly useful asan alternative to conventional NSAIDs where such NSAIDs arecontraindicated, for example in patients with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; gastrointestinalbleeding, coagulation disorders including anemia such ashypoprothrombinemia, hemophilia or other bleeding problems; kidneydisease; or in patients prior to surgery or patients takinganticoagulants.

[0175] Such compositions are useful to treat a variety of arthriticdisorders, including but not limited to rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis.

[0176] Such compositions are also useful in treatment of asthma,bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis,allergic neuritis, cytomegalovirus infectivity, apoptosis includingHIV-induced apoptosis, lumbago, liver disease including hepatitis,skin-related conditions such as psoriasis, eczema, acne, bums,dermatitis and ultraviolet radiation damage including sunburn, andpost-operative inflammation including that following ophthalmic surgerysuch as cataract surgery or refractive surgery.

[0177] Such compositions are useful to treat gastrointestinal conditionssuch as inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome and ulcerative colitis.

[0178] Such compositions are useful in treating inflammation in suchdiseases as migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, neuromuscular junction disease including myasthenia gravis,white matter disease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,nephritis, hypersensitivity, swelling occurring after injury includingbrain edema, myocardial ischemia, and the like.

[0179] Such compositions are useful in treatment of ophthalmic diseases,such as retinitis, conjunctivitis, retinopathies, uveitis, ocularphotophobia, and of acute injury to the eye tissue.

[0180] Such compositions are useful in treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis, and in bone resorption such as that associated withosteoporosis.

[0181] Such compositions are useful for treatment of certain centralnervous system disorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and central nervous systemdamage resulting from stroke, ischemia and trauma. The term “treatment”in the present context includes partial or total inhibition ofdementias, including Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholic dementia andsenile dementia.

[0182] Such compositions are useful in treatment of allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome and liverdisease.

[0183] Such compositions are useful in treatment of pain, including butnot limited to postoperative pain, dental pain, muscular pain, and painresulting from cancer. For example, such compositions are useful forrelief of pain, fever and inflammation in a variety of conditionsincluding rheumatic fever, influenza and other viral infectionsincluding common cold, low back and neck pain, dysmenorrhea, headache,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, andtrauma following surgical and dental procedures.

[0184] Such compositions are useful for treating and preventinginflammation-related cardiovascular disorders, including vasculardiseases, coronary artery disease, aneurysm, vascular rejection,arteriosclerosis, atherosclerosis including cardiac transplantatherosclerosis, myocardial infarction, embolism, stroke, thrombosisincluding venous thrombosis, angina including unstable angina, coronaryplaque inflammation, bacterial-induced inflammation includingChlamydia-induced inflammation, viral induced inflammation, andinflammation associated with surgical procedures such as vasculargrafting including coronary artery bypass surgery, revascularizationprocedures including angioplasty, stent placement, endarterectomy, orother invasive procedures involving arteries, veins and capillaries.

[0185] Such compositions are useful in treatment of angiogenesis-relateddisorders in a subject, for example to inhibit tumor angiogenesis. Suchcompositions are useful in treatment of neoplasia, including metastasis;ophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,macular degeneration, retrolental fibroplasia and neovascular glaucoma;ulcerative diseases such as gastric ulcer; pathological, butnon-malignant, conditions such as hemangiomas, including infantilehemangiomas, angiofibroma of the nasopharynx and avascular necrosis ofbone; and disorders of the female reproductive system such asendometriosis.

[0186] Such compositions are useful in prevention and treatment ofbenign and malignant tumors and neoplasia including cancer, such ascolorectal cancer, brain cancer, bone cancer, epithelial cell-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer, stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,cervical cancer, lung cancer, breast cancer, skin cancer such assquamous cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body. Neoplasias for which compositions of the inventionare contemplated to be particularly useful are gastrointestinal cancer,Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer,ovarian cancer, prostate cancer, cervical cancer, lung cancer, breastcancer and skin cancer. Such compositions can also be used to treatfibrosis that occurs with radiation therapy. Such compositions can beused to treat subjects having adenomatous polyps, including those withfamilial adenomatous polyposis (FAP). Additionally, such compositionscan be used to prevent polyps from forming in patients at risk of FAP.

[0187] Such compositions inhibit prostanoid-induced smooth musclecontraction by inhibiting synthesis of contractile prostanoids and hencecan be of use in treatment of dysmenorrhea, premature labor, asthma andeosinophil-related disorders. They also can be of use for decreasingbone loss particularly in postmenopausal women (i.e., treatment ofosteoporosis), and for treatment of glaucoma.

[0188] Because of the rapid onset of therapeutic effect that can beexhibited by compositions of the invention, these compositions haveparticular advantages over prior formulations for treatment of acuteCOX-2 mediated disorders, especially for relief of pain, for example inheadache, including sinus headache and migraine.

[0189] Preferred uses for compositions of the present invention are fortreatment of rheumatoid arthritis and osteoarthritis, for painmanagement generally (particularly post-oral surgery pain, post-generalsurgery pain, post-orthopedic surgery pain, and acute flares ofosteoarthritis), for prevention and treatment of headache and migraine,for treatment of Alzheimer's disease, and for colon cancerchemoprevention.

[0190] For treatment of rheumatoid arthritis or osteoarthritis, suchcompositions of the invention can be used to provide a daily dosage ofcelecoxib of about 50 mg to about 1000 mg, preferably about 100 mg toabout 600 mg, more preferably about 150 mg to about 500 mg, still morepreferably about 175 mg to about 400 mg, for example about 200 mg. Adaily dose of celecoxib of about 0.7 to about 13 mg/kg body weight,preferably about 1.3 to about 8 mg/kg body weight, more preferably about2 to about 6.7 mg/kg body weight, and still more preferably about 2.3 toabout 5.3 mg/kg body weight, for example about 2.7 mg/kg body weight, isgenerally appropriate when administered in a composition of theinvention. The daily dose can be administered in one to about four dosesper day, preferably one or two doses per day.

[0191] For treatment of Alzheimer's disease or cancer, such compositionsof the invention can be used to provide a daily dosage of celecoxib ofabout 50 mg to about 1000 mg, preferably about 100 mg to about 800 mg,more preferably about 150 mg to about 600 mg, and still more preferablyabout 175 mg to about 400 mg, for example about 400 mg. A daily dose ofabout 0.7 to about 13 mg/kg body weight, preferably about 1.3 to about10.7 mg/kg body weight, more preferably about 2 to about 8 mg/kg bodyweight, and still more preferably about 2.3 to about 5.3 mg/kg bodyweight, for example about 5.3 mg/kg body weight, is generallyappropriate when administered in a composition of the invention. Thedaily dose can be administered in one to about four doses per day,preferably one or two doses per day.

[0192] For pain management generally and specifically for treatment andprevention of headache and migraine, such compositions of the inventioncan be used to provide a daily dosage of celecoxib of about 50 mg toabout 1000 mg, preferably about 100 mg to about 600 mg, more preferablyabout 150 mg to about 500 mg, and still more preferably about 175 mg toabout 400 mg, for example about 200 mg. A daily dose of celecoxib ofabout 0.7 to about 13 mg/kg body weight, preferably about 1.3 to about 8mg/kg body weight, more preferably about 2 to about 6.7 mg/kg bodyweight, and still more preferably about 2.3 to about 5.3 mg/kg bodyweight, for example about 2.7 mg/kg body weight, is generallyappropriate when administered in a composition of the invention. Thedaily dose can be administered in one to about four doses per day.Administration at a rate of one 50 mg dose unit four times a day, one100 mg dose unit or two 50 mg dose units twice a day or one 200 mg doseunit, two 100 mg dose units or four 50 mg dose units once a day ispreferred.

[0193] For selective COX-2 inhibitory drugs other than celecoxib,appropriate doses can be selected by reference to the patent literaturecited hereinabove.

[0194] Besides being useful for human treatment, such compositions ofthe invention are useful for veterinary treatment of companion animals,exotic animals, farm animals, and the like, particularly mammals. Moreparticularly, such compositions of the invention are useful fortreatment of COX-2 mediated disorders in horses, dogs and cats.

[0195] This embodiment of the invention is further directed to atherapeutic method of treating a condition or disorder where treatmentwith a COX-2 inhibitory drug is indicated, the method comprising oraladministration of a composition of the invention to a subject in needthereof. The dosage regimen to prevent, give relief from, or amelioratethe condition or disorder preferably corresponds to once-a-day ortwice-a-day treatment, but can be modified in accordance with a varietyof factors. These include the type, age, weight, sex, diet and medicalcondition of the subject and the nature and severity of the disorder.Thus, the dosage regimen actually employed can vary widely and cantherefore deviate from the preferred dosage regimens set forth above.

[0196] Initial treatment can begin with a dose regimen as indicatedabove. Treatment is generally continued as necessary over a period ofseveral weeks to several months or years until the condition or disorderhas been controlled or eliminated. Subjects undergoing treatment with acomposition of the invention can be routinely monitored by any of themethods well known in the art to determine effectiveness of therapy.Continuous analysis of data from such monitoring permits modification ofthe treatment regimen during therapy so that optimally effective dosesare administered at any point in time, and so that the duration oftreatment can be determined. In this way, the treatment regimen anddosing schedule can be rationally modified over the course of therapy sothat the lowest amount of the composition exhibiting satisfactoryeffectiveness is administered, and so that administration is continuedonly for so long as is necessary to successfully treat the condition ordisorder.

[0197] Compositions of the present embodiment can be used in combinationtherapies with opioids and other analgesics, including narcoticanalgesics, Mu receptor antagonists, Kappa receptor antagonists,non-narcotic (i.e. non-addictive) analgesics, monoamine uptakeinhibitors, adenosine regulating agents, cannabinoid derivatives,Substance P antagonists, neurokinin-1 receptor antagonists and sodiumchannel blockers, among others. Preferred combination therapies compriseuse of a composition of the invention with one or more compoundsselected from aceclofenac, acemetacin, e-acetamidocaproic acid,acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid(aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine,alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate),amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid,2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammoniumsalicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine,antipyrine salicylate, antrafenine, apazone, bendazac, benorylate,benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen,bezitramide, α-bisabolol, bromfenac, p-bromoacetanilide,5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid,bucolome, bufexamac, bumadizon, buprenorphine, butacetin, butibufen,butophanol, calcium acetylsalicylate, carbamazepine, carbiphene,carprofen, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate,cinchophen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene,clonixin, clopirac, clove, codeine, codeine methyl bromide, codeinephosphate, codeine sulfate, cropropamide, crotethamide, desomorphine,dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium,difenamizole, difenpiramide, diflunisal, dihydrocodeine,dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminumacetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol,droxicam, emorfazone, enfenamic acid, epirizole, eptazocine, etersalate,ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene,ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac,fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac,fepradinol, feprazone, floctafenine, flufenamic acid, flunoxaprofen,fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisicacid, glafenine, glucametacin, glycol salicylate, guaiazulene,hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac,isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone,ketoprofen, ketorolac, p-lactophenetide, lefetamine, levorphanol,lofentanil, lonazolac, lomoxicam, loxoprofen, lysine acetylsalicylate,magnesium acetylsalicylate, meclofenamic acid, mefenamic acid,meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride,methotrimeprazine, metiazinic acid, metofoline, metopon, mofebutazone,mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate,morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthylsalicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone,niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilide,norlevorphanol, normethadone, normorphine, norpipanone, olsalazine,opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine,perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridinehydrochloride, phenocoll, phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,piketoprofen, piminodine, pipebuzone, piperylone, piprofen, pirazolac,piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine,promedol, propacetamol, propiram, propoxyphene, propyphenazone,proquazone, protizinic acid, ramifenazone, remifentanil, rimazoliummetilsulfate, salacetamide, salicin, salicylamide, salicylamide o-aceticacid, salicylsulfuric acid, salsalte, salverine, simetride, sodiumsalicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase,suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine,tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol,xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck Index,12th Edition (1996), Therapeutic Category and Biological Activity Index,lists therein headed “Analgesic”, “Anti-inflammatory” and“Antipyretic”).

[0198] Particularly preferred combination therapies comprise use of acomposition of this embodiment with an opioid compound, moreparticularly where the opioid compound is codeine, meperidine, morphineor a derivative thereof.

[0199] The compound to be administered in combination with a selectiveCOX-2 inhibitory drug can be formulated separately from the drug orco-formulated with the drug in a composition of the invention. Where aselective COX-2 inhibitory drug is co-formulated with a second drug, forexample an opioid drug, the second drug can be formulated inimmediate-release, rapid-onset, sustained-release or dual-release form.

[0200] In an embodiment of the invention, particularly where the COX-2mediated condition is headache or migraine, the present selective COX-2inhibitory drug composition is administered in combination therapy witha vasomodulator, preferably a xanthine derivative having vasomodulatoryeffect, more preferably an alkylxanthine compound.

[0201] Combination therapies wherein an alkylxanthine compound isco-administered with a selective COX-2 inhibitory drug composition asprovided herein are embraced by the present embodiment of the inventionwhether or not the alkylxanthine is a vasomodulator and whether or notthe therapeutic effectiveness of the combination is to any degreeattributable to a vasomodulatory effect. The term “alkylxanthine” hereinembraces xanthine derivatives having one or more C₁₋₄ alkyl, preferablymethyl, substituents, and pharmaceutically acceptable salts of suchxanthine derivatives. Dimethylxanthines and trimethylxanthines,including caffeine, theobromine and theophylline, are especiallypreferred. Most preferably, the alkylxanthine compound is caffeine.

[0202] The total and relative dosage amounts of the selective COX-2inhibitory drug and of the vasomodulator or alkylxanthine are selectedto be therapeutically and/or prophylactically effective for relief ofpain associated with the headache or migraine. Suitable dosage amountswill depend on the particular selective COX-2 inhibitory drug and theparticular vasomodulator or alkylxanthine selected. For example, in acombination therapy with celecoxib and caffeine, typically the celecoxibwill be administered in a daily dosage amount of about 50 mg to about1000 mg, preferably about 100 mg to about 600 mg, and the caffeine in adaily dosage amount of about 1 mg to about 500 mg, preferably about 10mg to about 400 mg, more preferably about 20 mg to about 300 mg.

[0203] The vasomodulator or alkylxanthine component of the combinationtherapy can be administered in any suitable dosage form by any suitableroute, preferably orally. The vasomodulator or alkylxanthine canoptionally be coformulated with the selective COX-2 inhibitory drug in asingle oral dosage form. Thus a solution or solution/suspensionformulation of the invention optionally comprises both anaminosulfonyl-comprising selective COX-2 inhibitory drug and avasomodulator or alkylxanthine such as caffeine, in total and relativeamounts consistent with the dosage amounts set out hereinabove.

[0204] The phrase “in total and relative amounts effective to relievepain”, with respect to amounts of a selective COX-2 inhibitory drug anda vasomodulator or alkylxanthine in a composition of the presentembodiment, means that these amounts are such that (a) together thesecomponents are effective to relieve pain, and (b) each component is orwould be capable of contribution to a pain-relieving effect if the othercomponent is or were not present in so great an amount as to obviatesuch contribution.

EXAMPLES Example 1

[0205] Six celecoxib solution formulations SF-1 to SF-6 were preparedhaving components as shown in Table 1. In each case the solvent liquidconsisted of PEG-400, either alone (SF-1) or together with at least onefree radical-scavenging antioxidant (SF-2 to SF-6). Celecoxib waspresent in solution at a concentration of 50 mg/g in all formulations.Antioxidant amounts are shown as % weight/weight. TABLE 1 Composition ofcelecoxib solution formulations SF-1 to SF-6 Formulation Components SF-1Celecoxib, PEG-400 SF-2 Celecoxib, PEG-400, 0.1% vitamin E SF-3Celecoxib, PEG-400, 0.1% BHA SF-4 Celecoxib, PEG-400, 0.1% BHT SF-5Celecoxib, PEG-400, 0.1% propyl gallate SF-6 Celecoxib, PEG-400, 0.05%BHA, 0.05% BHT

Example 2

[0206] A gradient HPLC assay was used to determine impurities incelecoxib solution formulations SF-1 to SF-6 of Example 1 after storageat various temperatures for different periods of time. Solutionformulation samples were drawn and were dissolved in methanol to obtaina celecoxib concentration of about 0.4 to about 0.5 mg/ml prior toinjection. Chromatographic conditions were as follows: (a) flow rate: 1ml/min.; (b) detection: UV 254 nm; (c) injection volume: 10 μl; (d)column: 5 μm Supercosil, LC-DP, 250×4.6 mm; (e) column temperature: 40°C.; (f) mobile phase A: 10 mM NH₄AC or KH₂PO₄, pH 3; (g) mobile phase B:100% acetonitrile; (h) running time: 45 minutes. Data are shown inTables 2 and 3. TABLE 2 Impurity level (%) in formulations SF-1 to SF-5following storage days stored at 70° C. Formulation 9 14 16 20 28 33 3590 SF-1 2.9 3.7 7.6 12.6 SF-2 0.02 0.02 0.02 2.8  SF-3 0.02 0.02 0.020.09 SF-4 0.03 0.04 0.06 0.30 SF-5 ND ND ND 0.15

[0207] TABLE 3 Impurity level (%) in formulations SF-1, SF-2, SF-5 andSF-6 following storage at different temperatures Temperature FormulationDays 50° C. 40° C. 25° C. 4° C. SF-1 0 0.00 0.00 0.00 0.00 7 0.09 214.12 0.11 0.00 31 6.25 0.00 74 7.83 5.40 0.08 0.00 131 7.85 6.87 0.440.00 SF-2 0 0.00 0.00 0.00 0.00 7 0.00 21 0.02 0.00 0.00 31 0.01 0.00 740.06 0.02 0.00 0.00 131 0.07 0.01 0.00 0.00 SF-5 0 0.00 0.00 0.00 0.00 70.02 21 0.05 0.03 0.02 31 0.05 0.00 74 0.15 0.11 0.03 0.00 131 0.20 0.090.02 0.00 SF-6 0 0.00 0.00 0.00 0.00 7 0.00 21 0.01 0.01 0.00 31 0.010.00 74 0.03 0.02 0.01 0.00 131 0.06 0.01 0.00 0.00

[0208] The data in Tables 2 and 3 indicate that the presence of a smallamount of a free radical-scavenging antioxidant such as vitamin E, butylgallate, BHA or BHT greatly improves chemical stability of celecoxibdissolved in PEG-400 by comparison with compositions comprising no suchantioxidant.

Example 3

[0209] Solution formulation SF-1 of Example 1 was bubbled with ethyleneoxide, a putative source of free radicals, for 15 minutes, and was thenstored at 70° C. for 10 days. After storage, the formulation wasanalyzed for the presence of impurities. Addition compounds detectedtherein were isolated by reversed-phase, semi-preparative HPLC. A 20×250mm Kromasil C18 column was employed with either an isocratic or agradient, acetonitrile-aqueous trifluoroacetic acid mobile phase.Detection was accomplished at 254 nm. Pooled fractions containingindividual addition compounds, herein referred to as Peak 1, Peak 2 andPeak 3 addition compounds, were concentrated, desalted and reduced inchemical noise-causing components by trapping on a 7×300 mm HamiltonPRP-1 column. The eluent from the trapping column containing theindividual addition compounds was freeze-dried to yield the finalisolates. Peak 1 addition compound was 99% pure and Peak 2 additioncompound was >99% pure by analytical HPLC. Peak 3 addition compound was81% pure by analytical HPLC.

[0210] Analytical HPLC was also used to collect analytical scale peakcuts for mass spectrometric analysis on a PE Sciex Q-Star Qq-TOF massspectrometer. Survey and product ion scans, as well as high resolutionmass measurements for empirical formula determination were acquired inμESI (micro-electrospray ionization) mode. High resolution mass spectralinformation on Peak 1 and Peak 2 addition compounds were obtained on aFinnigan MAT-900ST mass spectrometer operating in μESI mode. Accuratemass measurement for Peak 1 addition compound was carried out by linearE-scan peak matching at a resolution of 7,400 (m/Am 10% valleydefinition) using the reference ions from PEG-400, (C₂H₄O)₉H₂ONa at437.23627 and (C₂H₄O)₁₀H₂ONa at 481.26248 daltons, respectively, tomatch against the sample pseudo-molecular ion. Accurate mass measurementfor Peak 2 addition compound was carried out by linear E-scan peakmatching at a resolution of 7,100 (m/Am 10% valley definition) using thereference ions from PEG-400 (C₂H₄O)₈H₂ONa at 393.21005 and (C₂H₄O)₉H₂ONaat 437.23627 daltons, respectively, to match against the samplepseudo-molecular ion.

[0211] NMR samples were prepared in a nitrogen glove box and dissolvedin 150 μl dimethyl sulfoxide-d₆. Data were acquired on a Varian INOVA400 NMR spectrometer operating at a proton frequency of 399.80 MHz, andequipped with a Nalorac inverse geometry, micro-gradient probe.Experiments were used directly from the vendor's standard library withno modifications.

[0212] Peak 1

[0213] Celecoxib and Peak 1 addition compound were individually mountedon gold-coated microscope slides for IR and Raman analyses. Micro-IRspecular reflectance data were collected from 4000→650 cm⁻¹ at 4-cm⁻¹resolution on a Nicolet 760 spectrometer equipped with a liquid nitrogencooled MCT detector. Sensitivity, expressed as instrument gain, was 8.Data were processed as a Fourier transform utilizing a Happ-Genzelapodization function and plotted as % transmittance vs. frequency. Thefinal spectra were the sum of 200 individual scans. Micro-Raman datawere collected from 3700→100 cm⁻¹ on a Nicolet 960 FT-Ramanspectrometer, equipped with a liquid nitrogen cooled germanium detector.Sensitivity, expressed as instrument gain, was 64. Data were processedas a Fourier transform utilizing a Happ-Genzel apodization function andplotted as absorbance vs. frequency. The final spectra were the sum of10,000 individual scans.

[0214] The molecular weight of Peak 1 addition compound was found to be469 daltons, 88 daltons heavier than celecoxib and indicative ofaddition of two ethanolic moieties. The molecular weight was confirmedby high resolution peak matching, of an analytical peak cut, as469.12831 daltons, within 0.2 ppm of theory for C₂₁H₂₂F₃N₃O₄S. Theaccurate mass of Peak 1 addition compound, less the ionizing proton, wasmeasured as 469.12826 daltons. The empirical formula for best fit usingthe valence rules was C₂₁H₂₂F₃N₃O₄S and within 0.1 ppm in mass fromtheory, thus confirming the molecular weight of this product. Peak 1addition compound is believed to beN,N-bis(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,having the structure (V):

[0215] NMR analysis of Peak 1 addition compound produced similar data tothose for the bulk drug. A major difference existed in the absence ofthe —SO₂NH₂ protons, and the inclusion of resonances consistent with thepresence of two —CH₂CH₂OH functionalities. The methylene protons andcarbons exhibited distinct chemical shifts that are consistent with theproposed structure.

[0216] The IR and Raman spectra of celecoxib and Peak 1 additioncompound are very similar, indicating that the bulk of the structure isthe same as that of celecoxib. Several spectral differences, however,between the two molecules are evident. The two N—H stretching vibrationsin the spectrum of celecoxib at 3236 and 3342 cm⁻¹ are missing in thedata for Peak 1 addition compound, indicating the amino group present incelecoxib is not present in Peak 1 addition compound. The N—H vibrationsin the IR spectrum for celecoxib are replaced by an intense, broadabsorbance centered at 3430 cm⁻¹ in the analogous data for Peak 1addition compound. This broad band is typical of an O—H stretch, but ismuch too intense to result from a single hydroxyl group, indicating thatPeak 1 addition compound possesses at least two OH groups, in place ofthe NH₂ group present in celecoxib. Another major spectral differencebetween the vibrational spectra for celecoxib and Peak 1 additioncompound are the presence of Raman C—H stretching vibrational bands forPeak 1 addition compound at 2967 and 2991 cm⁻¹ that are not present inthe analogous data for celecoxib. These differences indicate thepresence of additional CH₂ groups in the addition compound, compared tocelecoxib. Both the IR and Raman data are consistent with the proposedstructure.

[0217] The compound having the structure (V) is believed to be new andis useful as an analytical marker, for example in detecting stability ofcelecoxib in pharmaceutical compositions where the celecoxib is or hasbeen exposed to polyethylene glycol or ethylene oxide, and/or as aselective cyclooxygenase-2 inhibitory drug or a pro-drug thereof.

[0218] Peak 2

[0219] The molecular weight of Peak 2 addition compound was found to be425 daltons, 44 daltons heavier than celecoxib and indicative of theaddition of one ethanolic moiety. The molecular weight was confirmed byhigh resolution peak matching, of an analytical peak cut, as 425.10239daltons, within 0.9 ppm of theory for C₁₉H₁₈F₃N₃O₃S. The accurate massof Peak 2 addition compound, less the ionizing proton, was measured as425.10168 daltons. The empirical formula for best fit using the valencerules was C₁₉H₁₈F₃N₃O₃S and within 1.0 ppm in mass from theory, thusconfirming the molecular weight of this compound. Peak 2 additioncompound is believed to beN-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,having the structure (VI):

[0220] The NMR data for Peak 2 addition compound were similar to thosefor Peak 1 addition compound in that this isolate also exhibited the—CH₂CH₂OH functionality, but proton integrations identified the presenceof only one ethanol substituent. The presence of an —NH— group was alsoapparent in the proton spectrum. The proton and carbon chemical shiftswere in accordance with the proposed structure.

[0221] The compound having the structure (VI) is believed to be new andis useful as an analytical marker, for example in detecting stability ofcelecoxib in pharmaceutical compositions where the celecoxib is or hasbeen exposed to polyethylene glycol or ethylene oxide, and/or as aselective cyclooxygenase-2 inhibitory drug and/or a pro-drug thereof.

[0222] Peak 3

[0223] Peak 3 addition compound was present in insufficientconcentration for an adequate isolate to be obtained for spectroscopicanalysis.

Example 4

[0224] Three celecoxib (10 mg/g) solutions (with methanol as solvent),one containing no peroxide (S1), one containing 150 ppm hydrogenperoxide (S2), and one containing 150 ppm t-butyl-peroxide (S3), wereprepared. HPLC analysis, as described in Example 2, was performed todetermine the presence or absence of impurities following storage atdifferent temperatures for various periods of time (Table 4). TABLE 4Chemical stability of celecoxib solutions S1-S3 Total impurity level (%)Solution Time 4° C. 25° C. 59° C. S1 0 0.15 0.15 0.15 1 week 0.15 0.150.54 2 weeks 0.14 1.57 3 weeks, then 3 days at 70° C. 2.40 S2 0 0.150.15 0.15 1 week 0.15 0.15 0.46 2 weeks 0.14 0.94 3 weeks, then 3 daysat 70° C. 1.60 S3 0 0.15 0.15 0.15 1 week 0.15 0.15 0.33 2 weeks 0.130.92 3 weeks, then 3 days at 70° C. 2.00

[0225] These data indicate that the presence of hydrogen peroxide ort-butyl-peroxide at a concentration of 150 ppm does not affect celecoxibstability in methanol. These data are consistent with the conclusionthat chemical instability in a system comprising anaminosulfonyl-comprising drug, for example celecoxib, and a polyethyleneglycol, is not peroxide-mediated.

Example 5

[0226] Two celecoxib solution formulations, SF-7, and SF-8, and twovehicle (placebo) solution formulations, SF-9 and SF-10, were preparedhaving components shown in Table 5. TABLE 5 Composition (mg) of solutionformulations SF-7 to SF-10 Component SF-7 SF-8 SF-9 SF-10 Celecoxib 200 200  Water USP 26 26 26 26 HPMC (E5) 38 38 Ethanol 113  100  113  100 PEG-400 271  322  271  322  Polyvinylpyrrolidone 47 47 47 47 Polysorbate80 217  217  217  217  Tromethamine 26 26 26 26 Oleic acid 61 61 61 61Propyl gallate NF  1  1  1  1 Total 1000  1000  800  800 

[0227] After storage for 90 days at different temperatures, the fractionof the initial 1 mg/g propyl gallate remaining in each formulation wasmeasured via gradient HPLC. Sample of all formulations were dissolved inmethanol to obtain a suitable concentration prior to injection.Chromatographic conditions were as follows: (a) flow rate: 1 ml/min.;(b) detection: UV 254 nm; (c) injection volume: 15 μl; (d) column: 3.5μm Zorbax XBD-C8, 50×4.6 mm; (e) column temperature: 25° C.; (f) mobilephase A: 0.1% TFA in water; (g) mobile phase B: 0.1% TFA inacetonitrile; (h) running time: 16 minutes. Data are shown in Table 6.TABLE 6 Loss of propyl gallate in solution formulations SF-7 to SF-10after storage for 90 days Propyl gallate (% of theoretical) remainingTemperature (° C.) SF-7 SF-8 SF-9 SF-10  4 87 104 108 126 25 42 74 36 6640 10 33 10 24 50 0 13 0 19 70 0 0 0 7

[0228] These data indicate that, in formulations comprising anaminosulfonyl-comprising drug (celecoxib in the present example) and inthose without such a drug, propyl gallate is consumed at a substantiallyequal rate over 90 days. Moreover, the rate of consumption istemperature dependent with increasing rate as temperature increases.These results suggest that the free radical-scavenging antioxidant isconsumed via a non drug-mediated mechanism, and support the presenttheory that drug stabilization results from an interaction betweenpolyethylene glycol degradation products and the free radical-scavengingantioxidant.

Example 6

[0229] A celecoxib solution formulation, SF-11, was prepared having thecomposition shown in Table 7. TABLE 7 Composition (mg/g) of celecoxibsolution formulation SF-11 Component SF-11 Celecoxib 200 Water USP 26HPMC (E5) 38 Ethanol 113 PEG 400 271 PVP 47 Polysorbate 80 217Tromethamine 26 Oleic acid 61 Propyl gallate NF 1 Total 1000

[0230] One gram of formulation SF-11 was individually placed into eachof several hard gelatin capsules (Capsugel) to form Test Composition 1.

[0231] A celecoxib suspension for comparative purposes was prepared asfollows:

[0232] A. Tween™ 80, 5.0 g, was placed in a volumetric flask.

[0233] B. Ethanol was added (to 100 ml) to form a mixture and themixture was swirled to form a uniform solution.

[0234] C. A 5 ml aliquot of the uniform solution was transferred to afresh 100 ml bottle containing 200 mg celecoxib, to form a premix.

[0235] D. Apple juice, 75 ml, was added to the premix to form anintermediate celecoxib suspension.

[0236] E. The intermediate celecoxib suspension was left to stand for 5minutes, and was then shaken to form a celecoxib suspension forcomparative purposes.

[0237] Bioavailability parameters resulting from administration of TestComposition 1, in comparison with the comparative celecoxib suspensioncomposition of Example 5 and with a commercial celecoxib (Celebrex® ofPharmacia) 200 mg capsule, to human subjects were evaluated in a24-subject, randomized, four period, balanced, crossover study. A fourthcomposition, not relevant to the present invention, was also included inthe study but is not reported here. Study duration was approximately 15days and subjects were randomly given one of each of the four dosageforms on days 1, 5, 9 and 12; administration of each dose was precededby an 8 hour fasting period and was accompanied by 180 ml of water.Plasma blood levels for each subject were measured at pre-dose and at15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours afterdosage administration. C_(max) and AUC were calculated from the data inaccordance with standard procedure in the art. As shown in Table 8,ingestion of Test Composition 1 resulted in a C_(max) more than 2.5times greater than resulted from ingestion of the comparative celecoxibsuspension or the commercial celecoxib capsule. Ingestion of TestComposition 1 also resulted in an AUC 43% greater than, and a T_(max)substantially similar to, that resulting from ingestion of thecomparative celecoxib suspension. TABLE 8 In vivo bioavailability ofcelecoxib in human subjects Commercial Comparative Test compositionParameter capsule suspension 1 C_(max) (ng/ml) 621 804 2061 T_(max) (hr)2.15 0.97 1.03 AUC (ng/ml)*hr 5060 4892 7593

Example 7

[0238] Two celecoxib solution formulations, SF-12 and SF-13, and twoplacebo solution formulations, P-2 and P-3, were prepared havingcompositions shown in Table 9. TABLE 9 Composition (mg) of celecoxibsolution formulations SF-12 and SF-13 and placebo solution formulationsP-2 and P-3 Component SF-12 SF-13 P-2 P-3 Celecoxib 100 200 — — WaterUSP 13 26 15.1 30.2 HPMC (E5) 19 38 22.1 44.2 Ethanol 56.5 113 65.7131.4 PEG 400 135.5 271 157.5 315 PVP 23.5 47 27.3 54.6 Polysorbate 80108.5 217 126.1 252.3 Tromethamine 13 26 15.1 30.2 Oleic acid 30.5 6135.5 70.9 Propyl gallate NF 0.5 1 0.6 1.2 Total 500 1000 465 930

[0239] Amounts of 500 mg and 1000 mg of solution formulations SF-12 andSF-13 respectively were individually placed into each of several softgelatin capsules to form Test Compositions 2 (100 mg celecoxib) and 3(200 mg celecoxib), respectively. Test Composition 4 consisted of twocapsules of Test Composition 3 resulting in a 400 mg celecoxib dose.Placebo solution formulations P-2 and P-3 were filled into soft capsulescorresponding in size with those containing solution formulations SF-12and SF-13, respectively, to form Placebo Composition 2 and PlaceboComposition 3.

[0240] A randomized, double-blind, active and placebo controlled,single-dose parallel group study was performed in order to assess theanalgesic efficacy of Test Compositions 2, 3 and 4 in comparison withappropriate and visually matching placebo, in a human post-oral surgerypain model.

[0241] Post-surgical patients (after extraction of two or more impactedthird molars requiring bone removal) who reported moderate or severepost-oral surgery pain on a categorical pain scale (CPS; 0=no pain,1=mild pain, 2=moderate pain, and 3=severe pain), and a baseline painintensity ≧50 mm on a visual analog scale (VAS; whereby patient locatesa sliding bar representing his or her level of pain on a 100 mmhorizontal scale with the left edge (0 mm) marked “no pain” and theright edge (100 mm) marked “worst pain”) within 6 hours after completionof surgery were selected and randomized for study.

[0242] Each patient was randomized to one of four treatment groups(approximately 55 per group) and, 6 hours after completion of surgery,received the study medication assigned to his or her group from bothBottle A and Bottle B as shown in the medication schedule found in Table10. Two additional compositions, not illustrative of the presentinvention, were also included in the study but are not reported here.TABLE 10 Schedule of study medication given to patients in treatmentgroups 1-4 Treatment Group Bottle A (1 capsule) Bottle B (2 capsules) 1.(Placebo) 1 × Placebo Composition 2 2 × Placebo Composition 3 2. (Test 1× Test Composition 2 2 × Placebo Composition 3 composition 2) 3. (Test 1× Placebo Composition 2 1 × Placebo Composition 3 composition 3) and 1 ×Test Composition 3 4. (Test 1 × Placebo Composition 2 2 × TestComposition 3 composition 4)

[0243] Pain was assessed at baseline (0 hour), 0.25, 0.50. 0.75, 1.0,1.25, 1.50, 1.75, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, and 24 hoursafter administration of study medication. Each patient individuallydetermined and recorded time to perceptible pain relief and time tomeaningful pain relief, using two stopwatches.

[0244] Time to onset of analgesia was then calculated for each patientby performing a time-to-event analysis combining data from patient'sstopwatch assessments of time to perceptible and meaningful pain relief.Baseline pain intensity for each group is shown in Table 11. Median timeto onset of analgesia is shown in Table 12. TABLE 11 Baseline painintensity Test Test Test Pain Scale Composition 2 Composition 3Composition 4 CPS (%) Moderate 56 56 57 Severe 44 44 43 VAS 0 to 100 mmMean 73.29 72.78 73.86

[0245] These data show that patients in each test group had comparablebaseline pain intensity. TABLE 12 Median time to onset of analgesiaTreatment Time (min) Placebo >1440 Test Composition 2 31 TestComposition 3 28 Test Composition 4 31

[0246] As determined in a similar pain study reported in InternationalPatent Publication No. WO 01/91750, incorporated herein by reference,200 mg Celebrex® capsules exhibit a median time to onset of analgesia of41 minutes. The data in Table 12 show that patients taking TestCompositions 2, 3 or 4 experienced a relatively fast median time toonset of analgesia of 31 minutes or less.

What is claimed is:
 1. An orally deliverable pharmaceutical compositioncomprising (a) a drug of low water solubility in a therapeuticallyand/or prophylactically effective amount and (b) a solvent liquid thatcomprises at least one pharmaceutically acceptable polyethylene glycoland at least one pharmaceutically acceptable free radical-scavengingantioxidant, wherein a substantial portion of the drug is in dissolvedor solubilized form in the solvent liquid, and wherein the drugcomprises an aminosulfonyl functional group and/or is capable ofreacting with a polyethylene glycol or with a polyethylene glycoldegradation product to form an addition compound.
 2. The composition ofclaim 1 wherein the drug is a selective cyclooxygenase-2 inhibitorydrug.
 3. The composition of claim 2 wherein the selectivecyclooxygenase-2 inhibitory drug is a compound of formula

where R⁴ is hydrogen or a C₁₋₄ alkyl or alkoxy group, X is N or CR⁵where R⁵ is hydrogen or halogen, and Y and Z are independently carbon ornitrogen atoms defining adjacent atoms of a five- to six-membered ringthat is unsubstituted or substituted at one or more positions with oxo,halo, methyl or halomethyl groups.
 4. The composition of claim 3 whereinthe five- to six-membered ring is selected from the group consisting ofcyclopentenone, furanone, methylpyrazole, isoxazole and pyridine ringssubstituted at no more than one position.
 5. The composition of claim 2wherein the drug is selected from the group consisting of celecoxib,deracoxib, valdecoxib and JTE-522.
 6. The composition of claim 2 whereinthe drug is celecoxib.
 7. The composition of claim 2 wherein the drug isvaldecoxib.
 8. The composition of claim 2 that further comprises avasomodulator, wherein the selective cyclooxygenase-2 inhibitory drugand the vasomodulator are present in total and relative amountseffective to relieve pain in headache or migraine.
 9. The composition ofclaim 2 that further comprises an alkylxanthine compound, wherein theselective cyclooxygenase-2 inhibitory drug and the alkylxanthinecompound are present in total and relative amounts effective to relievepain in headache or migraine.
 10. The composition of claim 9 wherein thealkylxanthine compound is caffeine.
 11. The composition of claim 1wherein the polyethylene glycol has an average molecular weight of about100 to about 10,000.
 12. The composition of claim 1 wherein thepolyethylene glycol is of liquid grade.
 13. The composition of claim 1wherein the at least one free radical-scavenging antioxidant is presentin the solvent liquid in a total amount of about 0.01% to about 5% byweight of the composition.
 14. The composition of claim 1 wherein the atleast one free radical-scavenging antioxidant is present in the solventliquid in a total amount of about 0.01% to about 1% by weight of thecomposition.
 15. The composition of claim 1 wherein the at least onefree radical-scavenging antioxidant is selected from the groupconsisting of vitamin E, ascorbic acid and salts thereof, butylatedhydroxyanisole, butylated hydroxytoluene, fumaric acid and saltsthereof, hypophosphorous acid, malic acid, alkyl gallates, sodiumthiosulfate, sodium sulfite, sodium bisulfite and sodium metabisulfite.16. The composition of claim 1 wherein the at least one freeradical-scavenging antioxidant is propyl gallate.
 17. The composition ofclaim 1 wherein the at least one free radical-scavenging antioxidant isvitamin E.
 18. The composition of claim 1 wherein substantially all ofthe drug present in the composition is in dissolved or solubilized form.19. The composition of claim 1 wherein the solvent liquid furthercomprises a turbidity-decreasing polymer.
 20. The composition of claim19 wherein the at least one turbidity-decreasing polymer ishydroxypropylmethylcellulose.
 21. The composition of claim 1 wherein thesolvent liquid further comprises at least one pharmaceuticallyacceptable fatty acid and at least one pharmaceutically acceptableorganic amine.
 22. The composition of claim 21 wherein the at least onefatty acid is oleic acid.
 23. The composition of claim 21 wherein the atleast one organic amine is a tertiary amine selected from the groupconsisting of triethanolamine and dimethylaminoethanol.
 24. Thecomposition of claim 1 that comprises one or more discrete dose units,wherein a therapeutically and/or prophylactically effective amount ofthe drug is contained in one to a small plurality of said dose units.25. The composition of claim 24 wherein each dose unit is aliquid-filled capsule having a capsule wall.
 26. The composition ofclaim 25 wherein the capsule wall comprises a turbidity-decreasingpolymer.
 27. The composition of claim 26 wherein theturbidity-decreasing polymer is hydroxypropylmethylcellulose.
 28. Amethod of treating a medical condition or disorder in a subject wheretreatment with a cyclooxygenase-2 inhibitor is indicated, comprisingorally administering to the subject a composition of claim
 2. 29. Amethod of analgesia comprising orally administering an effectivepain-relieving amount of a composition of claim 2 to a subject in needof analgesia.
 30. The method of claim 29 wherein the subject suffersfrom headache or migraine and wherein there is further orallyadministered to the subject a vasomodulator, the selectivecyclooxygenase-2 inhibitory drug and the vasomodulator beingadministered in total and relative amounts effective to relieve pain inthe headache or migraine.
 31. The method of claim 29 wherein the subjectsuffers from headache or migraine and wherein there is further orallyadministered to the subject an alkylxanthine compound, the selectivecyclooxygenase-2 inhibitory drug and the alkylxanthine compound beingadministered in total and relative amounts effective to relieve pain inthe headache or migraine.
 32. A method of use of a composition of claim2 in manufacture of a medicament useful for treating a medical conditionor disorder in a subject where treatment with a cyclooxygenase-2inhibitor is indicated.